U.S. patent number 6,720,427 [Application Number 10/144,403] was granted by the patent office on 2004-04-13 for thiazole derivatives.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to Christopher B. Cooper, Chris J. Helal, Mark A. Sanner.
United States Patent |
6,720,427 |
Sanner , et al. |
April 13, 2004 |
Thiazole derivatives
Abstract
The invention provides compounds of formula 1 ##STR1## wherein
R.sup.1, R.sup.3, and R.sup.4 are as defined, and their
pharmaceutically acceptable salts. Compounds of formula 1 are
indicated to have activity inhibiting cdk5, cdk2, and GSK-3.
Pharmaceutical compositions and methods comprising compounds of
formula 1 for treating diseases and conditions comprising abnormal
cell growth, such as cancer, and neurodegenerative diseases and
conditions and those affected by dopamine neurotransmission are
described. Also described are pharmaceutical compositions and
methods comprising compounds of formula 1 for treating male
fertility and sperm motility; diabetes mellitus; impaired glucose
tolerance; metabolic syndrome or syndrome X; polycystic ovary
syndrome; adipogenesis and obesity; myogenesis and frailty, for
example age-related decline in physical performance; acute
sarcopenia, for example muscle atrophy and/or cachexia associated
with burns, bed rest, limb immobilization, or major thoracic,
abdominal, and/or orthopedic surgery; sepsis; hair loss, hair
thinning, and balding; and immunodeficiency.
Inventors: |
Sanner; Mark A. (Old Saybrook,
CT), Helal; Chris J. (Mystic, CT), Cooper; Christopher
B. (Lawrenceville, NJ) |
Assignee: |
Pfizer Inc. (New York,
NY)
|
Family
ID: |
23116124 |
Appl.
No.: |
10/144,403 |
Filed: |
May 13, 2002 |
Current U.S.
Class: |
548/193; 546/142;
546/153; 546/167; 548/190; 548/196; 548/195; 548/191; 546/270.7;
546/162; 546/148; 546/143; 546/146 |
Current CPC
Class: |
A61P
37/04 (20180101); C07D 417/14 (20130101); A61P
21/00 (20180101); A61P 3/04 (20180101); C07D
277/46 (20130101); A61P 15/08 (20180101); A61P
17/14 (20180101); A61P 25/00 (20180101); A61P
25/28 (20180101); A61P 17/02 (20180101); C07D
277/42 (20130101); A61P 3/10 (20180101); A61P
37/00 (20180101); A61P 3/06 (20180101); A61P
7/00 (20180101); C07D 277/48 (20130101); A61P
35/00 (20180101); C07D 417/12 (20130101); C07D
277/62 (20130101); A61P 43/00 (20180101); C07D
277/64 (20130101) |
Current International
Class: |
C07D
277/64 (20060101); C07D 417/14 (20060101); C07D
277/42 (20060101); C07D 417/00 (20060101); C07D
277/46 (20060101); C07D 277/48 (20060101); C07D
277/00 (20060101); C07D 417/12 (20060101); C07D
277/62 (20060101); C07D 217/22 (); C07D 215/16 ();
C07D 277/04 (); C07D 277/18 (); C07D 277/38 () |
References Cited
[Referenced By]
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Martin et al. |
6114365 |
September 2000 |
Pevarello et al. |
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Aug 1998 |
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EP |
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WO 98/28257 |
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WO |
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Other References
Khimicheskii Zhurnal Armenii (2001), vol. 54 No. 1-2, pp. 110-114,
CODEN: KZARF3; ISSN: 1561-4190. .
Grehn L., A method for nitration of thiazoles, Journal of
Heterocyclic Chemistry, vol. 14, No. 5, Aug. 1977, pp. 917-919.
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Erlenmeyer H. et al., Uber einige derivate des 2-Aminothiazols,
Helvetica Chimica ACTA, vol. 32, No. 1, Feb. 1, 1949, pp. 35-38.
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Chemical Abstracts, vol. 47, No. 8, Apr. 25, 1953, abstract No.
38541. .
Ganapathi, K., et al., Chemotherapy of malaria. V. Synthesis of
4-(thiazolyamino)quinolines and 4-phenoxyquinolines & Proc.
Indian Acad. Sci., vol. 34A, 1951, pp. 178-182. .
Nagano, M. et al., "Studies on organic sulfur compounds. IX. The
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|
Primary Examiner: Seaman; D. Margaret
Attorney, Agent or Firm: Richardson; P. C. Ling; L. B.
Konstas; K. L.
Parent Case Text
This application claims priority under 35 U.S.C. 119(e) of U.S.
Application No. 60/290,466, filed May 11, 2001.
Claims
What is claimed is:
1. A compound of the formula ##STR7##
wherein R.sup.1 is a straight chain or branched (C.sub.2
-C.sub.8)alkyl, a straight chain or branched (C.sub.2
-C.sub.8)alkenyl, a straight chain or branched (C.sub.2
-C.sub.8)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14) aryl, (5-14
membered) heteroaryl, or ABN-; and wherein R.sup.1 is optionally
substituted with from one to six substituents R.sup.5 independently
selected from F, Cl, Br, I, nitro, cyano, --CF.sub.3, --NR.sup.7
R.sup.8, --NR.sup.7 C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8,
--NR.sup.7 C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2
R.sup.8, --NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; A and B are each independently
selected from straight or branched (C.sub.1 -C.sub.8)alkyl,
straight chain or branched (C.sub.2 -C.sub.8)alkenyl, straight
chain or branched (C.sub.2 -C.sub.8)alkynyl, (C.sub.3
-C.sub.6)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (3-8 membered)
heterocycloalkyl, (C.sub.5 -C.sub.11)bicycloalkyl, (C.sub.7
-C.sub.11)bicycloalkenyl, and (5-11 membered) heterocycloalkyl; or
A and B may be connected to form a 3-8 membered heterocyclic ring
optionally containing one or two double bonds and optionally
containing one or two further hetero atoms selected independently
from O, S, and N; and A and B, or the heterocyclic ring formed
thereby, can be optionally independently substituted with from one
to six substituents R.sup.5 independently selected from F, Cl, Br,
I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; R.sup.3 is --C(.dbd.O)NR.sup.9 --,
--C(.dbd.O)O--, --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --, or
--(CR.sup.10 R.sup.11).sub.n --; R.sup.4 is a straight chain or a
branched (C.sub.1 -C.sub.8)alkyl, a straight chain or a branched
(C.sub.2 -C.sub.8)alkenyl, a straight chain or branched (C.sub.2
-C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, or (5-14
membered) heteroaryl; and wherein R.sup.4 is optionally substituted
with from one to three substituents R.sup.6 independently selected
from F, Cl, Br, I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8,
--NR.sup.7 C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8,
--NR.sup.7 C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2
R.sup.8,--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, or R.sup.7 ; each R.sup.7, R.sup.8, and R.sup.9
is independently selected from H, straight chain or branched
(C.sub.1 -C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.7, R.sup.8, and R.sup.9 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.10 R.sup.11, --NR.sup.10
C(.dbd.O)R.sup.11, --NR.sup.10 C(.dbd.O)OR.sup.11, --NR.sup.10
C(.dbd.O)NR.sup.11 R.sup.12, --NR.sup.10 S(.dbd.O).sub.2 R.sup.11,
--NR.sup.10 S(.dbd.O).sub.2 NR.sup.11 R.sup.12, --OR.sup.10,
OC(.dbd.O)R.sup.10, --OC(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.10
R.sup.11, --OC(.dbd.O)SR.sup.10, --SR.sup.10, --S(.dbd.O)R.sup.10,
--S(.dbd.O).sub.2 R.sup.10, --S(.dbd.O).sub.2 NR.sup.10 R.sup.11,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.10
R.sup.11, and R.sup.10 ; or, when R.sup.7 and R.sup.8 are as in
NR.sup.7 R.sup.8, they may instead optionally be connected to form
with the nitrogen of NR.sup.7 R.sup.8 to which they are attached a
heterocycloalkyl moiety of from three to seven ring members, said
heterocycloalkyl moiety optionally comprising one or two further
heteroatoms independently selected from N, O, and S; each R.sup.10,
R.sup.11, and R.sup.12 is independently selected from H, straight
chain or branched (C.sub.1 -C.sub.8)alkyl, straight chain or
branched (C.sub.2 -C.sub.8)alkenyl, straight chain or branched
(C.sub.2 -C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.10, R.sup.11, and R.sup.12 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.13 R.sup.14, --NR.sup.13
C(.dbd.O)R.sup.14, --NR.sup.13 C(.dbd.O)OR.sup.14, --NR.sup.13
C(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.13 S(.dbd.O).sub.2 R.sup.14,
--NR.sup.13 S(.dbd.O).sub.2 NR.sup.14 R.sup.15, --OR.sup.13,
--OC(.dbd.O)R.sup.13, --OC(.dbd.O)OR.sup.13, --OC(.dbd.O)NR.sup.13
R.sup.14, --OC(.dbd.O)SR.sup.13, --SR.sup.13, --S(.dbd.O)R.sup.13,
--S(.dbd.O).sub.2 R.sup.13, --S(.dbd.O).sub.2 NR.sup.13 R.sup.14,
--C(.dbd.O)R.sup.13, --C(.dbd.O)OR.sup.13, --C(.dbd.O)NR.sup.13
R.sup.14, and R.sup.13 ; each R.sup.13, R.sup.14, and R.sup.15 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.13, R.sup.14, and R.sup.15 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.16 R.sup.17, --NR.sup.16
C(.dbd.O)R.sup.17, --NR.sup.16 C(.dbd.O)OR.sup.17, --NR.sup.16
C(.dbd.O)NR.sup.17 R.sup.18, --NR.sup.16 S(.dbd.O).sub.2 R.sup.17,
--NR.sup.16 S(.dbd.O).sub.2 NR.sup.17 R.sup.18, --OR.sup.16,
--OC(.dbd.O)R.sup.16, --OC(.dbd.O)OR.sup.16, --OC(.dbd.O)NR.sup.16
R.sup.17, --OC(.dbd.O)SR.sup.16, --SR.sup.16, --S(.dbd.O)R.sup.16,
--S(.dbd.O).sub.2 R.sup.16, --S(.dbd.O).sub.2 NR.sup.16 R.sup.17,
--C(.dbd.O)R.sup.16, --C(.dbd.O)OR.sup.16, --C(.dbd.O)NR.sup.16
R.sup.17, and R.sup.16 ; each R.sup.16, R.sup.17, and R.sup.18 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl; n is 0, 1, 2, or 3; wherein R.sup.10 and
R.sup.11 in --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n -- and
--(CR.sup.10 R.sup.11).sub.n -- are for each iteration of n defined
independently as recited above; or a pharmaceutically acceptable
salt thereof.
2. A compound according to claim 1, wherein R.sup.1 is cyclobutyl,
optionally substituted with from one to six substituents
R.sup.5.
3. A compound according to claim 2, wherein R.sup.3 is
--C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --.
4. A compound according to claim 1, wherein R.sup.1 is ABN-.
5. A compound according to claim 1, wherein R.sup.3 is --(CR.sup.10
R.sup.11).sub.0 -- and R.sup.4 is (3-8 membered) heterocycloalkyl,
(C.sub.6 -C.sub.14)aryl, or (5-14 membered) heteroaryl, and R.sup.4
is optionally substituted with from one to three substituents
R.sup.6.
6. A compound according to claim 5, wherein R.sup.4 is (C.sub.6
-C.sub.14)aryl or (5-14 membered) heteroaryl, each optionally
substituted.
7. A compound according to claim 6, wherein R.sup.4 is optionally
substituted phenyl or optionally substituted pyridyl.
8. A compound according to claim 6, wherein R.sup.4 is naphthyl,
quinolyl, or isoquinolyl, each optionally substituted.
9. A compound according to claim 6, wherein R.sup.4 is
unsubstituted napthyl, unsubstituted quinolyl, or unsubstituted
isoquinolyl.
10. A compound according to claim 1, wherein R.sup.3 is
--(CR.sup.10 R.sup.11).sub.0 -- and R.sup.1 is optionally
substituted straight chain or branched (C.sub.1 -C.sub.8)alkyl or
optionally substituted straight chain or branched (C.sub.2
-C.sub.8)alkenyl.
11. A compound according to claim 1, wherein R.sup.3 is
--C(.dbd.O)NR.sup.9 -- or --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n
--.
12. A compound according to claim 11, wherein R.sup.10 and R.sup.11
of --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n -- are at each iteration
of n both hydrogen and R.sup.9 of --C(.dbd.O)NR.sup.9 -- is
hydrogen.
13. A compound according to claim 1, wherein R.sup.1 is optionally
substituted (C.sub.3 -C.sub.8)cycloalkyl or optionally substituted
(C.sub.5 -C.sub.11) bicycloalkyl.
14. A compound according to claim 13, wherein R.sup.1 is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl,
each optionally substituted.
15. A compound according to claim 13, wherein R.sup.1 is (C.sub.3
-C.sub.8)cycloalkyl or optionally substituted (C.sub.5 -C.sub.11)
bicycloalkyl, and is optionally substituted with from one to three
substituents independently selected from F, Cl, Br, I, nitro,
cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7 C(.dbd.O)R.sup.8,
--OR.sup.7, --C(.dbd.O)OR.sup.7, --C(.dbd.O)R.sup.7, and
R.sup.7.
16. A compound according to claim 13, wherein R.sup.1 is (C.sub.3
-C.sub.8)cycloalkyl or (C.sub.5 -C.sub.11)bicycloalkyl, and R.sup.1
is substituted with --NR.sup.7 C(.dbd.O)R.sup.8, (C.sub.6
-C.sub.14)aryl, (3-8 membered) heterocycloalkyl, or (5-14 membered)
heteroaryl, and wherein said aryl, heterocycloalkyl, and heteroaryl
are each optionally substituted with from one to six substituents
independently selected from F, Cl, Br, I, NO.sub.2, --CN,
--CF.sub.3, --NR.sup.10 R.sup.11, --NR.sup.10 C(.dbd.O)R.sup.11,
--NR.sup.10 C(.dbd.O)OR.sup.11, --NR.sup.10 C(.dbd.O)NR.sup.11
R.sup.12, --NR.sup.10 S(.dbd.O).sub.2 R.sup.11, --NR.sup.10
S(.dbd.O).sub.2 NR.sup.11 R.sup.12, --OR.sup.10,
--OC(.dbd.O)R.sup.10, --OC(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.10
R.sup.11, --OC(.dbd.O)SR.sup.10, --SR.sup.10, --S(.dbd.O)R.sup.10,
--S(.dbd.O).sub.2 R.sup.10, --S(.dbd.O).sub.2 NR.sup.10 R.sup.11,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.10
R.sup.11, and R.sup.10.
17. A compound according to claim 13, wherein R.sup.1 is
bicyclo-[3.1.0]-hexyl and is optionally substituted.
18. A compound according to claim 1, wherein R.sup.1 is optionally
substituted straight chain or branched (C.sub.2 -C.sub.8)alkyl or
optionally substituted straight chain or branched (C.sub.2
-C.sub.8)alkenyl.
19. A compound according to claim 1, wherein R.sup.4 is (C.sub.6
-C.sub.14)aryl or (5-14 membered) heteroaryl, each optionally
substituted.
20. A compound according to claim 19, wherein R.sup.4 is optionally
substituted phenyl or optionally substituted pyridyl.
21. A compound according to claim 19, wherein R.sup.4 is naphthyl,
quinolyl, or isoquinolyl, each optionally substituted.
22. A compound according to claim 19, wherein R.sup.4 is napthyl,
quinolyl, or isoquinolyl, and is unsubstituted.
23. A compound according to claim 1, selected from the group
consisting of: N-(5-cyclobutyl-thiazol-2-yl)-2-phenyl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-isobutyramide;
(5-cyclobutyl-thiazol-2-yl)-carbamic acid phenyl ester;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4-dichloro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,6-difluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(3-trifluoromethyl-phenyl)-urea;
1-(4-chloro-3-trifluoromethyl-phenyl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4,6-trifluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4-difluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-ethyl-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(3-phenoxy-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methoxy-phenyl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2,4-dichloro-phenyl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-phenyl-urea;
1-(4-bromo-3-trifluoromethyl-phenyl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methylsulfanyl-phenyl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(4-methoxy-phenyl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]
-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-6-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-quinolin-6-yl)-urea;
3-{2-[2-(2,4-dichloro-phenyl)-acetylamino]-thiazol-5-yl}-cyclobutanecarboxy
lic acid butyl ester;
N-(5-cyclobutyl-thiazol-2-yl)-2-pyridin-3-yl-acetamide;
3-{2-[2-(2,4-dichloro-phenyl)-acetylamino]-thiazol-5-yl}-cyclobutanecarboxy
lic acid;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-pyridin-3-yl-phenyl)-urea;
1-benzothiazol-5-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide;
1-(3H-benzotriazol-5-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-benzothiazol-5-yl)-urea;
1-biphenyl-3-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(3H-benzoimidazol-5-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-dimethylamino-ethylamino)-quinolin-6-
yl]-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(3-hydroxy-propylamino)-quinolin-6-yl]-u
rea; (5-cyclobutyl-thiazol-2-yl)-carbamic acid
3-(6-amino-quinolin-4-ylamino)-propyl ester;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2-methyl-benzothiazol-6-yl)-acetamide;
3-hydroxy-pyrrolidine-1-carboxylic acid
(5-cyclobutyl-thiazol-2-yl)-amide;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-hydroxy-cyclohexylamino)-quinolin-6-y
l]-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-5-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-6-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(3-hydroxy-pyrrolidin-1-yl)-quinolin-6-y
l]-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-5-yl-urea;
2-(1H-benzoimidazol-5-yl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-(5,6-dimethyl-benzoimidazol-1-yl)-acetamide
;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-hydroxy-cyclopentylamino)-quinolin-6-
yl]-urea; N-(5-cyclobutyl-thiazol-2-yl)-2-indol-1-yl-acetamide;
1-(3H-benzoimidazol-4-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(1H-indol-3-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-5-yl-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indazol-6-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methyl-2-oxo-1,2-dihydro-quinolin-7-yl)-
urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[2-(4-nitro-phenyl)-1H-benzoimidazol-5-yl]-
urea; 1-benzo[1,3]dioxol-5-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methoxymethyl-2-oxo-2H-chromen-7-yl)-ure
a;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methyl-2-oxo-2H-chromen-7-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-u
rea;
1-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4,7-dimethoxy-3H-benzoimidazol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-pyridin-2-yl-1H-benzoimidazol-5-yl)-urea
;
1-(5-cyclobutyl-thiazol-2-yl)-3-[2-(1,1,2,2,3,3,3-heptafluoro-propyl)-1H-be
nzoimidazol-5-yl]-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(6-fluoro-3-prop-2-ynyl-2-trifluoromethyl-3
H-benzoimidazol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-ur
ea; 1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-6-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-1H-benzoimidazol-5-yl)-urea;
5-[3-(5-cyclobutyl-thiazol-2-yl)-ureido]-1H-indole-2-carboxylic
acid ethyl ester;
1-benzo[1,2,3]thiadiazol-4-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-
yl)-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indazol-7-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-4-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-u
rea; 1-benzooxazol-4-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2-methyl-3H-benzoimidazol-5-yl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-8-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-8-yl-urea;
1-(3H-benzotriazol-4-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-isoquinolin-5-yl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-5-yl-urea;
N-[5-(3-acetylamino-cyclobutyl)-thiazol-2-yl]-2-quinolin-6-yl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-(4-nitro-phenyl)-acetamide;
2-(4-amino-phenyl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
2-(4-acetylamino-phenyl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-[4-(2-pyridin-3-yl-acetylamino)-phenyl]-ace
tamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-[4-(2-morpholin-4-yl-ethylamino)-phenyl]-ac
etamide; (5-isopropyl-thiazol-2-yl)-pyridin-2-yl-amine;
(3-chloro-5-trifluoromethyl-pyridin-2-yl)-(5-isopropyl-thiazol-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-phenyl-amine;
(5-chloro-pyridin-2-yl)-(5-isopropyl-thiazol-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(6-methyl-pyridin-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(5-methyl-pyridin-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(4-methyl-pyridin-2-yl)-amine;
(2-chloro-pyridin-4-yl)-(5-isopropyl-thiazol-2-yl)-amine; and
N-(5-dimethylamino-thiazol-2-yl)-2-phenyl-acetamide; and
pharmaceutically acceptable salts of the foregoing compounds.
24. A compound of the formula ##STR8## wherein R.sup.1 is a
straight chain or branched (C.sub.2 -C.sub.8)alkenyl, a straight
chain or branched (C.sub.2 -C.sub.8)alkynyl, (C.sub.3
-C.sub.8)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (3-8 membered)
heterocycloalkyl, (C.sub.5 -C.sub.11)bicycloalkyl, (C.sub.7
-C.sub.11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl,
(C.sub.6 -C.sub.14) aryl, (5-14 membered) heteroaryl, or ABN-; and
wherein R.sup.1 is optionally substituted with from one to six
substituents R.sup.5 independently selected from F, Cl, Br, I,
nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.7 R.sup.8, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; A and B are each independently
selected from straight or branched (C.sub.1 -C.sub.8)alkyl,
straight chain or branched (C.sub.2 -C.sub.8)alkenyl, straight
chain or branched (C.sub.2 -C.sub.8)alkynyl, (C.sub.3
-C.sub.6)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (3-8 membered)
heterocycloalkyl, (C.sub.5 -C.sub.11)bicycloalkyl, (C.sub.7
-C.sub.11)bicycloalkenyl, and (5-11 membered) heterocycloalkyl; or
A and B may be connected to form a 3-8 membered heterocyclic ring
optionally containing one or two double bonds and optionally
containing one or two further hetero atoms selected independently
from O, S, and N; and A and B, or the heterocyclic ring formed
thereby, can be optionally independently substituted with from one
to six substituents R.sup.5 independently selected from F, Cl, Br,
I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; R.sup.3 is --C(.dbd.O)NR.sup.9 --,
--C(.dbd.O)O--, --C(.dbd.O)(CR.sup.10 OR.sup.11).sub.n --, or
--(CR.sup.10 R.sup.11).sub.n --; R.sup.4 is a straight chain or a
branched (C.sub.1 -C.sub.8)alkyl, a straight chain or a branched
(C.sub.2 -C.sub.8)alkenyl, a straight chain or branched (C.sub.2
-C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, or (5-14
membered) heteroaryl; and wherein R.sup.4 is optionally substituted
with from one to three substituents R.sup.6 independently selected
from F, Cl, Br, I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8,
--NR.sup.7 C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8,
--NR.sup.7 C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2
R.sup.8, --NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, or R.sup.7 ; each R.sup.7, R.sup.8, and R.sup.9
is independently selected from H, straight chain or branched
(C.sub.1 -C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.7, R.sup.8, and R.sup.9 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.10 R.sup.11, --NR.sup.10
C(.dbd.O)R.sup.11, --NR.sup.10 C(.dbd.O)OR.sup.11, --NR.sup.10
C(.dbd.O)NR.sup.11 R.sup.12, --NR.sup.10 S(.dbd.O).sub.2 R.sup.11,
--NR.sup.10 S(.dbd.O).sub.2 NR.sup.11 R.sup.12, --OR.sup.10,
OC(.dbd.O)R.sup.10, --OC(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.10
OR.sup.11, --OC(.dbd.O)SR.sup.10, --S(.dbd.O)R.sup.10,
--S(.dbd.O).sub.2 R.sup.10), --S(.dbd.O).sub.2 NR.sup.10 R.sup.11,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.10
OR.sup.11, and R.sup.10 ; or, when R.sup.7 and R.sup.8 are as in
NR.sup.7 R.sup.8, they may instead optionally be connected to form
with the nitrogen of NR.sup.7 R.sup.8 to which they are attached a
heterocycloalkyl moiety of from three to seven ring members, said
heterocycloalkyl moiety optionally comprising one or two further
heteroatoms independently selected from N, O, and S; each R.sup.10,
R.sup.11, and R.sup.12 is independently selected from H, straight
chain or branched (C.sub.1 -C.sub.8)alkyl, straight chain or
branched (C.sub.2 -C.sub.8)alkenyl, straight chain or branched
(C.sub.2 -C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.10, R.sup.11, and R.sup.12 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.13 R.sup.14, --NR.sup.13
C(.dbd.O)R.sup.14, --NR.sup.13 C(.dbd.O)OR.sup.14, --NR.sup.13
C(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.13 S(.dbd.O).sub.2 R.sup.14,
--NR.sup.13 S(.dbd.O).sub.2 NR.sup.14 R.sup.15, --OR.sup.13,
--OC(.dbd.O)R.sup.13, --OC(.dbd.O)OR.sup.13, --OC(.dbd.O)NR.sup.13
R.sup.14, --OC(.dbd.O)SR.sup.13, --SR.sup.13, --S(.dbd.O)R.sup.13,
--S(.dbd.O).sub.2 R.sup.13, --S(.dbd.O).sub.2 NR.sup.13 R.sup.14,
--C(.dbd.O)R.sup.13, --C(.dbd.O)OR.sup.13, --C(.dbd.O)NR.sup.13
R.sup.14, and R.sup.13 ; each R.sup.13, R.sup.14, and R.sup.15 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.13, R.sup.14, and R.sup.15 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.16 R.sup.17, --NR.sup.16
C(.dbd.O)R.sup.17, --NR.sup.16 C(.dbd.O)OR.sup.17, --NR.sup.16
C(.dbd.O)NR.sup.17 R.sup.18, --NR.sup.16 S(.dbd.O).sub.2 R.sup.17,
--NR.sup.16 S(.dbd.O).sub.2 NR.sup.17 R.sup.18, --OR.sup.16,
--OC(.dbd.O)R.sup.16, --OC(.dbd.O)OR.sup.16, --OC(.dbd.O)NR.sup.16
R.sup.17, --OC(.dbd.O)SR.sup.16, --SR.sup.16, --S(.dbd.O)R.sup.16,
--S(.dbd.O).sub.2 R.sup.16, --S(.dbd.O).sub.2 NR.sup.16 R.sup.17,
--C(.dbd.O)R.sup.16, --C(.dbd.O)OR.sup.16, --C(.dbd.O)NR.sup.16
R.sup.17, and R.sup.16 ; each R.sup.16, R.sup.17, and R.sup.18 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl; n is 0, 1, 2, or 3; wherein R.sup.10 and
R.sup.11 in --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n -- and
--(CR.sup.10 R.sup.11).sub.n -- are for each iteration of n defined
independently as recited above; or a pharmaceutically acceptable
salt thereof.
Description
FIELD OF THE INVENTION
The subject invention relates to thiazole derivatives,
pharmaceutical compositions comprising such derivatives and methods
of using such derivatives to treat abnormal cell growth and certain
diseases and conditions of the central nervous system. The
compounds of the present invention act as inhibitors of
cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent
protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The
compounds of the present invention also are inhibitors of the
enzyme GSK-3 (glygogen synthase kinase-3) enzyme.
BACKGROUND OF THE INVENTION
The serine/threonine kinase cdk5 along with its cofactor p25 (or
the longer cofactor, p35) has been linked to neurodegenerative
disorders, and inhibitors of cdk5/p25 (or cdk5/p35) are therefore
useful for the treatment of neurodegenerative disorders such as
Alzheimer's disease, Parkinson's disease, stroke, or Huntington's
disease. Treatment of such neurodegenerative disorders using cdk5
inhibitors is supported by the finding that cdk5 is involved in the
phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)).
cdk5 also phosphorylates Dopamine and Cyclic AMP-Regulated
Phosphorprotein (DARPP-32) at threonine 75 and is thus indicated in
having a role in dopaminergic neurotransmission (Nature, 402,
669-671 (1999)).
The serine/threonine kinase cdk2 is essential for normal cell
cycling and plays a critical role in disorders arising from
abnormal cell cycling, a common characteristic of many oncological
disorders. Inhibitors of cdk2 are therefore useful for the
treatment of various types of cancer and other diseases or
conditions related to abnormal cell growth (Meijer, et al.,
Properties and Potential-applications of Chemical Inhibitors of
Cyclin-dependent Kinsases, Pharmacology & therapeutics, 82
(2-3), 279-284 (1999); Sausville, et al., Cyclin-dependent Kinases:
Initial Approaches to Exploit a Novel Therapeutic Target,
Pharmacology & therapeutics 82 (2-3) 285-292 (1999)).
GSK-3 is a serine/threonine protein kinase. It is one of several
protein kinases which phosphorylate glycogen synthase (Embi, et
al., Eur. J. Biochem. 107:519-527 (1980); Hemmings, et al., Eur. J.
Biochem. 119:443-451 (1982)). GSK-3 exists in two isoforms, .alpha.
and .beta., in vertebrates, reported as having a monomeric
structure of 49 kD and 47 kD respectively. Both isoforms
phosphorylate muscle glycogen synthase (Cross, et al., Biochemical
Journal 303: 21-26 (1994)). The amino acid identity among GSK-3
species homologs has been indicated to be in excess of 98% within
the catalytic domain (Plyte, et al., Biochim. Biophys. Acta
1114:147-162) (1992)). Due to a remarkably high degree of
conservation across the phylogenetic spectrum, a fundamental role
of GSK-3 in cellular processes is suggested.
GSK-3 has been implicated in numerous different disease states and
conditions. For example, Chen, et al, Diabetes 43: 1234-1241 (1994)
have suggested that an increase in GSK-3 activity can be important
in Type 2 diabetes. Increased GSK-3 expression in diabetic muscle
is also though to contribute to the impaired glycogen synthase
activity and skeletal muscle insulin resistance present in Type 2
diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). Also, a
higher activity of a type 1 protein phosphatase measured in
immotile sperm was attributed to higher GSK-3 activity and was
indicated as responsible for holding the sperm motility in check
(Vijayaraghavan, et al. Biology of Reproduction 54: 709-718
(1996)). Vijayaraghavan et al. indicate that such results suggest a
biochemical basis for the development and regulation of sperm
motility and a possible physiological role for a protein
phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity has also
been associated with Alzheimer's disease and mood disorders such as
bipolar disorder (WO 97/41854). Among other conditions, GSK-3 has
furthermore been implicated in hair loss, schizophrenia, and
neurodegeneration, including both chronic neurodegenerative
diseases (such as Alzheimer's, supra) and neurotrauma, for example
stroke, traumatic brain injury, and spinal cord trauma.
SUMMARY OF THE INVENTION
This invention provides compounds of the formula ##STR2## wherein
R.sup.1 is a straight chain or branched (C.sub.1 -C.sub.8)alkyl, a
straight chain or branched (C.sub.2 -C.sub.8)alkenyl, a straight
chain or branched (C.sub.2 -C.sub.8)alkynyl, (C.sub.3
-C.sub.8)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (3-8 membered)
heterocycloalkyl, (C.sub.5 -C.sub.11)bicycloalkyl, (C.sub.7
-C.sub.11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl,
(C.sub.6 -C.sub.14) aryl, (5-14 membered) heteroaryl, or ABN-; and
wherein R.sup.1 is optionally substituted with from one to six
substituents R.sup.5 independently selected from F, Cl, Br, I,
nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; A and B are each independently
selected from straight or branched (C.sub.1 -C.sub.8)alkyl,
straight chain or branched (C.sub.2 -C.sub.8)alkenyl, straight
chain or branched (C.sub.2 -C.sub.8)alkynyl, (C.sub.3
-C.sub.6)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (3-8 membered)
heterocycloalkyl, (C.sub.5 -C.sub.11)bicycloalkyl, (C.sub.7
-C.sub.11)bicycloalkenyl, and (5-11 membered) heterocycloalkyl; or
A and B may be connected to form a 3-8 membered heterocyclic ring
optionally containing one or two double bonds and optionally
containing one or two further hetero atoms selected independently
from O, S, and N; and A and B, or the heterocyclic ring formed
thereby, can be optionally independently substituted with from one
to six substituents R.sup.5 independently selected from F, Cl, Br,
I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 OR.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7 ; R.sup.3 is --C(.dbd.O)NR.sup.9 --,
--C(.dbd.O)O--, --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --, or
--(CR.sup.10 R.sup.11).sub.n --; R.sup.4 is a straight chain or a
branched (C.sub.1 -C.sub.8)alkyl, a straight chain or a branched
(C.sub.2 -C.sub.8)alkenyl, a straight chain or branched (C.sub.2
-C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, or (5-14
membered) heteroaryl; and wherein R.sup.4 is optionally substituted
with from one to three substituents R.sup.6 independently selected
from F, Cl, Br, I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8,
--NR.sup.7 C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8,
--NR.sup.7 C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2
R.sup.8, --NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, or R.sup.7 ; each R.sup.7, R.sup.8, and R.sup.9
is independently selected from H, straight chain or branched
(C.sub.1 -C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.7, R.sup.8, and R.sup.9 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.10 R.sup.11, --NR.sup.10
C(.dbd.O)R.sup.11, --NR.sup.10 C(.dbd.O)OR.sup.11, --NR.sup.10
C(.dbd.O)NR.sup.11 R.sup.12, --NR.sup.10 S(.dbd.O).sub.2 R.sup.11,
--NR.sup.10 S(.dbd.O).sub.2 NR.sup.11 R.sup.12, --OR.sup.10,
OC(.dbd.O)R.sup.10, --OC(.dbd.O)OR.sup.10, --OC(.dbd.O)NR.sup.10
R.sup.11, --OC(.dbd.O)SR.sup.10, --SR.sup.10, --S(.dbd.O)R.sup.10,
--S(.dbd.O).sub.2 R.sup.10, --S(.dbd.O).sub.2 NR.sup.10 R.sup.11,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.10
R.sup.11, and R.sup.10 ; or, when R.sup.7 and R.sup.8 are as in
NR.sup.7 R.sup.8, they may instead optionally be connected to form
with the nitrogen of NR.sup.7 R.sup.8 to which they are attached a
heterocycloalkyl moiety of from three to seven ring members, said
heterocycloalkyl moiety optionally comprising one or two further
heteroatoms independently selected from N, O, and S; each R.sup.10,
R.sup.11, and R.sup.12 is independently selected from H, straight
chain or branched (C.sub.1 -C.sub.8)alkyl, straight chain or
branched (C.sub.2 -C.sub.8)alkenyl, straight chain or branched
(C.sub.2 -C.sub.8 alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.10, R.sup.11, and R.sup.12 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.13 R.sup.14, --NR.sup.13
C(.dbd.O)R.sup.14, --NR.sup.13 C(.dbd.O)OR.sup.14, --NR.sup.13
C(.dbd.O)NR.sup.14 R.sup.15, --NR.sup.13 S(.dbd.O).sub.2 R.sup.14,
--NR.sup.13 S(.dbd.O).sub.2 NR.sup.14 R.sup.15, --OR.sup.13,
--OC(.dbd.O)R.sup.13, --OC(.dbd.O)OR.sup.13, --OC(.dbd.O)NR.sup.13
R.sup.14, --OC(.dbd.O)SR.sup.13, --SR.sup.13, --S(.dbd.O)R.sup.13,
--S(.dbd.O).sub.2 R.sup.13, --S(.dbd.O).sub.2 NR.sup.13 R.sup.14,
--C(.dbd.O)R.sup.13, --C(.dbd.O)OR.sup.13, --C(.dbd.O)NR.sup.13
R.sup.14, and R.sup.13 ; each R.sup.13, R.sup.14, and R.sup.15 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl, wherein R.sup.13, R.sup.14, and R.sup.15 are
each independently optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, NO.sub.2,
--CN, --CF.sub.3, --NR.sup.16 R.sup.17, --NR.sup.16
C(.dbd.O)R.sup.17, --NR.sup.16 C(.dbd.O)OR.sup.17, --NR.sup.16
C(.dbd.O)NR.sup.17 R.sup.18, --NR.sup.16 S(.dbd.O).sub.2 R.sup.17,
--NR.sup.16 S(.dbd.O).sub.2 NR.sup.17 R.sup.18, --OR.sup.16,
--OC(.dbd.O)R.sup.16, --OC(.dbd.O)OR.sup.16, --OC(.dbd.O)NR.sup.16
R.sup.17, --OC(.dbd.O)SR.sup.16, --SR.sup.16, --S(.dbd.O)R.sup.16,
--S(.dbd.O).sub.2 R.sup.16, --S(.dbd.O).sub.2 NR.sup.16 R.sup.17,
--C(.dbd.O)R.sup.16, --C(.dbd.O)OR.sup.16, --C(.dbd.O)NR.sup.16
R.sup.17, and R.sup.16 ; each R.sup.16, R.sup.17, and R.sup.18 is
independently selected from H, straight chain or branched (C.sub.1
-C.sub.8)alkyl, straight chain or branched (C.sub.2
-C.sub.8)alkenyl, straight chain or branched (C.sub.2 -C.sub.8
alkynyl), (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4
-C.sub.8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.sub.5
-C.sub.11)bicycloalkyl, (C.sub.7 -C.sub.11)bicycloalkenyl, (5-11
membered) heterobicycloalkyl, (C.sub.6 -C.sub.14)aryl, and (5-14
membered) heteroaryl; n is 0, 1, 2, or 3; wherein R.sup.10 and
R.sup.11 in --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n -- and
--(CR.sup.10 R.sup.11).sub.n -- are for each iteration of n defined
independently as recited above; and pharmaceutically acceptable
salts thereof.
Compounds of formula 1 of the invention are inhibitors of
serine/threonine kinases, especially cyclin-dependent kinases such
as cdk5 and cdk2, and are useful for the treatment of
neurodegenerative disorders and other CNS disorders, and of
abnormal cell growth, including cancer. The compounds of formula 1
are particularly useful in inhibiting cdk5. Compounds of formula 1
are furthermore also useful as inhibitors of GSK-3.
The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight
or branched moieties. Examples of alkyl groups include, but are not
limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
The term "alkenyl", as used herein, unless otherwise indicated,
includes alkyl moieties having at least one carbon-carbon double
bond wherein alkyl is as defined above. Examples of alkenyl
include, but are not limited to, ethenyl and propenyl.
The term "alkynyl", as used herein, unless otherwise indicated,
includes alkyl moieties having at least one carbon-carbon triple
bond wherein alkyl is as defined above. Examples of alkynyl groups
include, but are not limited to, ethynyl and 2-propynyl.
The term "cycloalkyl", as used herein, unless otherwise indicated,
includes non-aromatic saturated cyclic alkyl moieties wherein alkyl
is as defined above. Examples of cycloalkyl include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl. "Bicycloalkyl" groups are non-aromatic saturated
carbocyclic groups consisting of two rings, wherein said rings
share one or two carbon atoms. For purposes of the present
invention, and unless otherwise indicated, bicycloalkyl groups
include spiro groups and fused ring groups. Examples of
bicycloalkyl groups include, but are not limited to,
bicyclo-[3.1.0]-hexyl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl,
spiro[4.3]octyl, and spiro[4.2]heptyl. "Cycloalkenyl" and
"bicycloalkenyl" refer to non-aromatic carbocyclic cycloalkyl and
bicycloalkyl moieties as defined above, except comprising one or
more carbon-carbon double bonds connecting carbon ring members (an
"endocyclic" double bond) and/or one or more carbon-carbon double
bonds connecting a carbon ring member and an adjacent non-ring
carbon (an "exocyclic" double bond). Examples of cycloalkenyl
groups include, but are not limited to, cyclopentenyl and
cyclobutenyl, and a non-limiting example of a bicycloalkenyl group
is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and
bicycloalkenyl groups also include groups that are substituted with
one or more oxo moieties. Examples of such groups with oxo moieties
are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and
norcamphoryl.
The term "aryl", as used herein, unless otherwise indicated,
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl, naphthyl, indenyl, and
fluorenyl.
The terms "heterocyclic", "heterocycloalkyl", and like terms, as
used herein, refer to non-aromatic cyclic groups containing one or
more heteroatoms, preferably from one to four heteroatoms, each
selected from O, S and N. "Heterobicycloalkyl" groups are
non-aromatic two-ringed cyclic groups, wherein said rings share one
or two atoms, and wherein at least one of the rings contains a
heteroatom (O, S, or N). Heterobicycloalkyl groups for purposes of
the present invention, and unless otherwise indicated, include
spiro groups and fused ring groups. In one embodiment, each ring in
the heterobicycloalkyl contains up to four heteroatoms (i.e. from
zero to four heteroatoms, provided that at least one ring contains
at least one heteroatom). The heterocyclic groups of this invention
can also include ring systems substituted with one or more oxo
moieties. Examples of non-aromatic heterocyclic groups are
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,
piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,
pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl,
1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl, and
1,4-dioxaspiro[4.2]heptyl.
"Heteroaryl", as used herein, refers to aromatic groups containing
one or more heteroatoms (O, S, or N), preferably from one to four
heteroatoms. A multicyclic group containing one or more heteroatoms
wherein at least one ring of the group is aromatic is a
"heteroaryl" group. The heteroaryl groups of this invention can
also include ring systems substituted with one or more oxo
moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl,
benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,
triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,
dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl,
furopyridinyl, pyrolopyrimidinyl, and azaindolyl.
The foregoing groups, as derived from the compounds listed above,
may be C-attached or N-attached where such is possible. For
instance, a group derived from pyrrole may be pyrrol-1-yl
(N-attached) or pyrrol-3-yl (C-attached). The terms referring to
the groups also encompass all possible tautomers.
In one embodiment, this invention provides compounds of formula 1,
wherein R.sup.1 is cyclobutyl, optionally substituted with from one
to six substituents R.sup.5 independently selected from F, Cl, Br,
I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7. In a further embodiment, R.sup.1 is
cyclobutyl and R.sup.3 is --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n
--.
In another embodiment of the invention, compounds of formula 1 are
provided wherein R.sup.1 is ABN-.
In another embodiment of the invention, compounds of formula 1 are
provided wherein R.sup.3 is --(CR.sup.10 R.sup.11).sub.0 -- (in
other words, R.sup.3 is a bond), and R.sup.4 is (3-8 membered)
heterocycloalkyl, (C.sub.6 -C.sub.14)aryl, or (5-14 membered)
heteroaryl, and R.sup.4 is optionally substituted with from one to
three substituents R.sup.6 independently selected from F, Cl, Br,
I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, or R.sup.7. In a further embodiment of compounds
of formula 1 wherein R.sup.3 is a bond, R.sup.4 is (C.sub.6
-C.sub.14)aryl or (5-14 membered) heteroaryl, each optionally
substituted. In a more preferred embodiment wherein R.sup.3 is a
bond, R.sup.4 is optionally substituted phenyl or optionally
substituted pyridyl. In another preferred embodiment wherein
R.sup.3 is a bond, R.sup.4 is naphthyl, quinolyl, or isoquinolyl,
each optionally substituted. In another embodiment wherein R.sup.3
is a bond, R.sup.4 is napthyl, quinolyl, or isoquinolyl, and is
unsubstituted.
In another embodiment of the invention, R.sup.3 is a bond and
R.sup.1 is optionally substituted straight chain or branched
(C.sub.1 -C.sub.8)alkyl or optionally substituted straight chain or
branched (C.sub.2 -C.sub.8)alkenyl
In another embodiment, this invention provides compounds of formula
1, wherein R.sup.3 is --C(.dbd.O)NR.sup.9 -- or
--C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --. In another embodiment,
R.sup.10 and R.sup.11 of --C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --
are at each iteration of n both hydrogen. In another embodiment,
R.sup.9 of --C(.dbd.O)NR.sup.9 -- is hydrogen. In another
embodiment, and R.sup.3 is --C(.dbd.O)NR.sup.9 -- or
--C(.dbd.O)(CR.sup.10 R.sup.11).sub.n --.
In another embodiment of the invention, a compound of formula 1 is
provided wherein R.sup.1 is optionally substituted (C.sub.3
-C.sub.8)cycloalkyl or optionally substituted (C.sub.5 -C.sub.11)
bicycloalkyl. Preferred embodiments are wherein R.sup.1 is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl,
each optionally substituted as recited above (i.e. optionally with
from one to six substituents R.sup.5 independently selected from F,
Cl, Br, I, nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.7 S(.dbd.O).sub.2 NR.sup.8 R.sup.9, --OR.sup.7,
--OC(.dbd.O)R.sup.7, --OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)R.sup.7, --C(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)SR.sup.7, --SR.sup.7,
--S(.dbd.O)R.sup.7, --S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2
NR.sup.7 R.sup.8, and R.sup.7). In a more preferred embodiment,
R.sup.1 is (C.sub.3 -C.sub.8)cycloalkyl or optionally substituted
(C.sub.5 -C.sub.11) bicycloalkyl, for example cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and is
optionally substituted with from one to three substituents
independently selected from F, Cl, Br, I, nitro, cyano, --CF.sub.3,
--NR.sup.7 R.sup.8, --NR.sup.7 C(.dbd.O)R.sup.8, --OR.sup.7,
--C(.dbd.O)OR.sup.7, --C(.dbd.O)R.sup.7, and R.sup.7. More
preferably, R.sup.1 is (C.sub.3 -C.sub.8)cycloalkyl or optionally
substituted (C.sub.5 -C.sub.11) bicycloalkyl, for example
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and
R.sup.1 is substituted with --NR.sup.7 C(.dbd.O)R.sup.8, (C.sub.6
-C.sub.14)aryl, (3-8 membered) heterocycloalkyl, or (5-14 membered)
heteroaryl, and wherein said aryl, heterocycloalkyl, and heteroaryl
are each optionally substituted with from one to six substituents
independently selected from F, Cl, Br, I, NO.sub.2, --CN,
--CF.sub.3, --NR.sup.10 R.sup.11, --NR.sup.10 C(.dbd.O)R.sup.11,
--NR.sup.10 C(.dbd.O)OR.sup.11, --NR.sup.10 C(.dbd.O)NR.sup.11
R.sup.12, --NR.sup.10 S(.dbd.O).sub.2 R.sup.11, --NR.sup.10
S(.dbd.O).sub.2 NR.sup.11 R.sup.12, --OR.sup.10,
--OC(.dbd.O)R.sup.10, --OC(.dbd.O)R.sup.10, --OC(.dbd.O)NR.sup.10
R.sup.11, --OC(.dbd.O)SR.sup.10, --SR.sup.10, --S(.dbd.O)R.sup.10,
--S(.dbd.O).sub.2 R.sup.10, --S(.dbd.O).sub.2 NR.sup.10 R.sup.11,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.10
R.sup.11, and R.sup.10. In another embodiment of the invention,
R.sup.1 is bicyclo[3.1.0]-hexyl and is optionally substituted as
recited above (i.e. optionally substituted with from one to six
substituents R.sup.5 independently selected from F, Cl, Br, I,
nitro, cyano, --CF.sub.3, --NR.sup.7 R.sup.8, --NR.sup.7
C(.dbd.O)R.sup.8, --NR.sup.7 C(.dbd.O)OR.sup.8, --NR.sup.7
C(.dbd.O)NR.sup.8 R.sup.9, --NR.sup.7 S(.dbd.O).sub.2 R.sup.8,
--NR.sup.8 R.sup.9, --OR.sup.7, --OC(.dbd.O)R.sup.7,
--OC(.dbd.O)OR.sup.7, --C(.dbd.O)OR.sup.7, --C(.dbd.O)R.sup.7,
--C(.dbd.O)NR.sup.7 R.sup.8, --OC(.dbd.O)NR.sup.7 R.sup.8,
--OC(.dbd.O)SR.sup.7, --SR.sup.7, --S(.dbd.O)R.sup.7,
--S(.dbd.O).sub.2 R.sup.7, --S(.dbd.O).sub.2 NR.sup.7 R.sup.8, and
R.sup.7).
In another embodiment of the invention, a compound of formula 1 is
provided wherein R.sup.1 is optionally substituted straight chain
or branched (C.sub.1 -C.sub.8)alkyl or optionally substituted
straight chain or branched (C.sub.2 -C.sub.8)alkenyl.
In another embodiment, this invention provides a compound of
formula 1 wherein R.sup.4 is (C.sub.6 -C.sub.14)aryl or (5-14
membered) heteroaryl, each optionally substituted. In a preferred
embodiment, R.sup.4 is optionally substituted phenyl or optionally
substituted pyridyl. In another preferred embodiment, R.sup.4 is
naphthyl, quinolyl, or isoquinolyl, each optionally substituted. In
another embodiment, R.sup.4 is napthyl, quinolyl, or isoquinolyl,
and is unsubstituted.
Examples of preferred compounds of formula 1 are:
N-(5-cyclobutyl-thiazol-2-yl)-2-phenyl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-isobutyramide;
(5-cyclobutyl-thiazol-2-yl)-carbamic acid phenyl ester;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4-dichloro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,6-difluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(3-trifluoromethyl-phenyl)-urea;
1-(4-chloro-3-trifluoromethyl-phenyl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4,6-trifluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2,4-difluoro-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-ethyl-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(3-phenoxy-phenyl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methoxy-phenyl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2,4-dichloro-phenyl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-phenyl-urea;
1-(4-bromo-3-trifluoromethyl-phenyl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methylsulfanyl-phenyl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(4-methoxy-phenyl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]
-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-6-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-quinolin-6-yl)-urea;
3-{2-[2-(2,4-dichloro-phenyl)-acetylamino]-thiazol-5-yl}-cyclobutanecarboxy
lic acid butyl ester;
N-(5-cyclobutyl-thiazol-2-yl)-2-pyridin-3-yl-acetamide;
3-{2-[2-(2,4-dichloro-phenyl)-acetylamino]-thiazol-5-yl}-cyclobutanecarboxy
lic acid;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-pyridin-3-yl-phenyl)-urea;
1-benzothiazol-5-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide;
1-(3H-benzotriazol-5-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-benzothiazol-5-yl)-urea;
1-biphenyl-3-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(3H-benzoimidazol-5-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-dimethylamino-ethylamino)-quinolin-6-
yl]-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(3-hydroxy-propylamino)-quinolin-6-yl]-u
rea; (5-cyclobutyl-thiazol-2-yl)-carbamic acid
3-(6-amino-quinolin-4-ylamino)-propyl ester;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2-methyl-benzothiazol-6-yl)-acetamide;
3-hydroxy-pyrrolidine-1-carboxylic acid
(5-cyclobutyl-thiazol-2-yl)-amide;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-hydroxy-cyclohexylamino)-quinolin-6-y
l]-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-5-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-6-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(3-hydroxy-pyrrolidine-1-yl)-quinolin-6-
yl]-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinol in-5-yl-urea;
2-(1H-benzoimidazol-5-yl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-(5,6-dimethyl-benzoimidazol-1-yl)-acetamide
;
1-(5-cyclobutyl-thiazol-2-yl)-3-[4-(2-hydroxy-cyclopentylamino)-quinolin-6-
yl]-urea; N-(5-cyclobutyl-thiazol-2-yl)-2-indol-1-yl-acetamide;
1-(3H-benzoimidazol-4-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(1H-indol-3-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-5-yl-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indazol-6-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methyl-2-oxo-1,2-dihydro-quinolin-7-yl)-
urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-[2-(4-nitro-phenyl)-1H-benzoimidazol-5-yl]-
urea; 1-benzo[1,3]dioxol-5-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methoxymethyl-2-oxo-2H-chromen-7-yl)-ure
a;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4-methyl-2-oxo-2H-chromen-7-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-u
rea;
1-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(4,7-dimethoxy-3H-benzoimidazol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-pyridin-2-yl-1H-benzoimidazol-5-yl)-urea
;
1-(5-cyclobutyl-thiazol-2-yl)-3-[2-(1,1,2,2,3,3,3-heptafluoro-propyl)-1H-be
nzoimidazol-5-yl]-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(6-fluoro-3-prop-2-ynyl-2-trifluoromethyl-3
H-benzoimidazol-5-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-ur
ea; 1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-6-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-methyl-1H-benzoimidazol-5-yl)-urea;
5-[3-(5-cyclobutyl-thiazol-2-yl)-ureido]-1H-indole-2-carboxylic
acid ethyl ester;
1-benzo[1,2,3]thiadiazol-4-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-5-
yl)-urea; 1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indazol-7-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(1H-indol-4-yl)-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-u
rea; 1-benzooxazol-4-yl-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-(2-methyl-3H-benzoimidazol-5-yl)-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-quinolin-8-yl-urea;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-8-yl-urea;
1-(3H-benzotriazol-4-yl)-3-(5-cyclobutyl-thiazol-2-yl)-urea;
N-(5-cyclobutyl-thiazol-2-yl)-2-isoquinolin-5-yl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide;
1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-5-yl-urea;
N-[5-(3-acetylamino-cyclobutyl)-thiazol-2-yl]-2-quinolin-6-yl-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-(4-nitro-phenyl)-acetamide;
2-(4-amino-phenyl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
2-(4-acetylamino-phenyl)-N-(5-cyclobutyl-thiazol-2-yl)-acetamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-[4-(2-pyridin-3-yl-acetylamino)-phenyl]-ace
tamide;
N-(5-cyclobutyl-thiazol-2-yl)-2-[4-(2-morpholin-4-yl-ethylamino)-phenyl]-ac
etamide; (5-isopropyl-thiazol-2-yl)-pyridin-2-yl-amine;
(3-chloro-5-trifluoromethyl-pyridin-2-yl)-(5-isopropyl-thiazol-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-phenyl-amine;
(5-chloro-pyridin-2-yl)-(5-isopropyl-thiazol-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(6-methyl-pyridin-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(5-methyl-pyridin-2-yl)-amine;
(5-isopropyl-thiazol-2-yl)-(4-methyl-pyridin-2-yl)-amine;
(2-chloro-pyridin-4-yl)-(5-isopropyl-thiazol-2-yl)-amine; and
N-(5-dimethylamino-thiazol-2-yl)-2-phenyl-acetamide; and
pharmaceutically acceptable salts of the foregoing compounds.
Salts of compounds of formula 1 can be obtained by forming salts
with any acidic or basic group present on a compound of formula 1.
Examples of pharmaceutically acceptable salts of the compounds of
formula 1 are the salts of hydrochloric acid, p-toluenesulfonic
acid, fumaric acid, citric acid, succinic acid, salicylic acid,
oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic
acid, tartaric acid, maleic acid, di-p-toluoyl tartaric acid,
acetic acid, sulfuric acid, hydroiodic acid, mandelic acid, sodium,
potassium, magnesium, calcium, and lithium.
The compounds of formula 1 may have optical centers and therefore
may occur in different enantiomeric and other stereoisomeric
configurations. The invention includes all enantiomers,
diastereomers, and other stereoisomers of such compounds of formula
1, as well as racemic and other mixtures thereof.
The subject invention also includes isotopically-labeled compounds,
which are identical to those recited in formula 1, but for the fact
that one or more atoms are replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine,
and chlorine, such as .sup.3 H, .sup.11 C, .sup.14 C, .sup.18 F,
.sup.123 I and .sup.125 I. Compounds of the present invention and
pharmaceutically acceptable salts of said compounds that contain
the aforementioned isotopes and/or other isotopes of other atoms
are within the scope of this invention. Isotopically-labeled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3 H and .sup.14 C are
incorporated, are useful in drug and/or substrate tissue
distribution assays. Tritiated, i.e., .sup.3 H, and carbon-14,
i.e., .sup.14 C, isotopes are particularly preferred for their ease
of preparation and detectability. .sup.11 C and .sup.18 F isotopes
are particularly useful in PET (positron emission tomography), and
.sup.125 I isotopes are particularly useful in SPECT (single photon
emission computerized tomography), all useful in brain imaging.
Further, substitution with heavier isotopes such as deuterium,
i.e., .sup.2 H, can afford certain therapeutic advantages resulting
from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labeled compounds of
formula 1 of this invention can generally be prepared by carrying
out the procedures disclosed in the Schemes and/or in the Examples
below, by substituting a readily available isotopically labeled
reagent for a non-isotopically labeled reagent.
This invention also provides a pharmaceutical composition for
treating a disease or condition comprising abnormal cell growth in
a mammal comprising a compound of formula 1 in an amount effective
in inhibiting abnormal cell growth, and a pharmaceutically
acceptable carrier.
This invention also provides a pharmaceutical composition for
treating a disease or condition comprising abnormal cell growth in
a mammal comprising a compound of formula 1 in an amount effective
to inhibit cdk2 activity, and a pharmaceutically acceptable
carrier.
This invention also provides a method for treating a disease or
condition comprising abnormal cell growth in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective in inhibiting abnormal cell growth.
This invention also provides a method for treating a diseases or
condition comprising abnormal cell growth in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective to inhibit cdk2 activity.
In a pharmaceutical composition or method of this invention for
treating a disease or condition comprising abnormal cell growth,
the disease or condition comprising abnormal cell growth is in one
embodiment cancer. The cancer may be a carcinoma, for example
carcinoma of the bladder, breast, colon, kidney, liver, lung, for
example small cell lung cancer, esophagus, gall bladder, ovary,
pancreas, stomach, cervix, thyroid, prostate, or skin, for example
squamous cell carcinoma; a hematopoietic tumor of lymphoid lineage,
for example leukemia, acute lymphocytic leukemia, B-cell lymphoma,
T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy
cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of
myeloid lineage, for example acute and chronic myelogenous
leukemias, myelodysplastic syndrome, or promyelocytic leukemia; a
tumor of mesenchymal origin, for example fibrosarcoma or
rhabdomyosarcoma; a tumor of the central or peripheral nervous
system, for example astrocytoma, neuroblastoma, glioma or
schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma;
xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer;
or Kaposi's sarcoma.
In another embodiment, the disease or condition comprising abnormal
cell growth is benign. Such diseases and conditions include benign
prostate hyperplasia, familial adenomatosis polyposis,
neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,
psoriasis, glomerulonephritis, restenosis, hypertrophic scar
formation, inflammatory bowel disease, transplantation rejection,
fungal infection, and endotoxic shock.
This invention also provides a pharmaceutical composition for
treating a neurodegenerative disease or condition in a mammal
comprising a compound of formula 1 in an amount effective in
treating said disease or condition, and a pharmaceutically
acceptable carrier.
This invention also provides a pharmaceutical composition for
treating a neurodegenerative disease or condition in a mammal
comprising a compound of formula 1 in an amount effective in
inhibiting cdk5 activity, and a pharmaceutically acceptable
carrier.
This invention also provides a method for treating a
neurodegenerative disease or condition in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective in inhibiting cdk5 activity.
This invention also provides a method for treating a
neurodegenerative disease or condition in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective in treating said disease or condition.
In one embodiment of the invention, the neurodegenerative disease
or condition which is treated is selected from Huntington's
disease, stroke, spinal cord trauma, traumatic brain injury,
multiinfarct dementia, epilepsy, amyotrophic lateral sclerosis,
pain, viral induced dementia for example AIDS induced dementia,
neurodegeneration associated with bacterial infection, migraine,
hypoglycemia, urinary incontinence, brain ischemia, multiple
sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's
type, mild cognitive impairment, age-related cognitive decline,
emesis, corticobasal degeneration, dementia pugilistica, Down's
syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease,
prion disease with tangles, progessive supranuclear palsy, lower
lateral sclerosis, and subacute sclerosing panencephalistis.
This invention also provides a pharmaceutical composition for
treating a disease or condition the treatment of which can be
effected or facilitated by altering dopamine mediated
neurotransmission in a mammal comprising a compound of formula 1 in
an amount effective in treating said disease or condition and a
pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for
treating a disease or condition the treatment of which can be
effected or facilitated by altering dopamine mediated
neurotransmission in a mammal comprising a compound of formula 1 in
an amount effective to inhibit cdk5 and a pharmaceutically
acceptable carrier.
This invention also provides a method for treating a disease or
condition the treatment of which can be effected or facilitated by
altering dopamine mediated neurotransmission in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective in inhibiting cdk5 activity.
This invention also provides a method for treating a disease or
condition the treatment of which can be effected or facilitated by
altering dopamine mediated neurotransmission in a mammal comprising
administering to the mammal a compound of formula 1 in an amount
effective in treating said disease or condition.
In one embodiment of the invention, the disease or condition the
treatment of which can be effected or facilitated by altering
dopamine mediated neurotransmission is selected from Parkinson's
disease; schizophrenia; schizophreniform disorder; schizoaffective
disorder, for example of the delusional type or the depressive
type; delusional disorder; substance-induced psychotic disorder,
for example psychosis induced by alcohol, amphetamine, cannabis,
cocaine, hallucinogens, inhalants, opioids, or phencyclidine;
personality disorder of the paranoid type; personality disorder of
the schizoid type; drug addiction, including narcotic (e.g. heroin,
opium, and morphine), cocaine and alcohol addiction; drug
withdrawal, including narcotic, cocaine and alcohol withdrawal;
obsessive compulsive disorder; Tourette's syndrome; depression; a
major depressive episode, a manic or mixed mood episode, a
hypomanic mood episode, a depressive episode with atypical features
or with melancholic features or catatonic features, a mood episode
with postpartum onset; post-stroke depression, major depressive
disorder, dysthymic disorder, minor depressive disorder,
premenstrual dysphoric disorder, post-psychotic depressive disorder
of schizophrenia, a major depressive disorder superimposed on a
psychotic disorder such as delusional disorder or schizophrenia, a
bipolar disorder, for example bipolar I disorder, bipolar II
disorder, cyclothymic disorder; anxiety; attention deficit and
hyperactivity disorder; and attention deficit disorder.
This invention also provides a method for treating a disease or
condition facilitated by cdk5 activity in a mammal which method
comprises administering to the mammal a compound of formula 1 in an
amount effective in inhibiting cdk5 activity.
We have also found that the compounds of formula 1 have activity in
inhibiting GSK-3. The compounds of formula I therefore can be
expected to be useful in treating diseases and conditions the
treatment of which can be effected or facilitated by inhibition of
GSK-3. Diseases and conditions the treatment of which can be
effected or facilitated by inhibiting GSK-3 include
neurodegenerative diseases and conditions. Neurodegenerative
diseases and conditions are discussed above and include, but are
not limited to, for example Alzheimer's disease, Parkinson's
disease, Huntington's disease, amyotrophic lateral sclerosis,
multiple sclerosis, stroke, cerebral ischemia, AIDS-related
dementia, neurodegeneration associated with bacterial infection,
multiinfarct dementia, traumatic brain injury, and spinal cord
trauma. Therefore, compounds of formula 1 are effective in treating
neurodegenerative diseases and conditions based on both cdk5
activity and GSK-3 activity.
Other diseases and conditions the treatment of which can be
effected or facilitated by inhibiting GSK-3 include psychotic
disorders and conditions, for example schizophrenia,
schizophreniform disorder; schizoaffective disorder, for example of
the delusional type or the depressive type; delusional disorder;
substance-induced psychotic disorder, for example psychosis induced
by alcohol, amphetamine, cannabis, cocaine, hallucinogens,
inhalants, opioids, or phencyclidine; personality disorder of the
paranoid type; and personality disorder of the schizoid type. The
treatment of such diseases and conditions can also be effected or
facilitated by altering dopamine mediated neurotransmission.
Therefore, compounds of formula 1 are effective in treating such
disorders and conditions based on both cdk5 activity and GSK-3
activity.
Other disorders and conditions the treatment of which can be
effected or facilitated by inhibiting GSK-3 include mood disorders
and mood episodes, for example a major depressive episode, a manic
or mixed mood episode, a hypomanic mood episode, a depressive
episode with atypical features or with melancholic features or
catatonic features, a mood episode with postpartum onset;
post-stroke depression, major depressive disorder, dysthymic
disorder, minor depressive disorder, premenstrual dysphoric
disorder, post-psychotic depressive disorder of schizophrenia, a
major depressive disorder superimposed on a psychotic disorder such
as delusional disorder or schizophrenia, a bipolar disorder, for
example bipolar I disorder, bipolar II disorder, and cyclothymic
disorder. The treatment of such mood disorders and episodes, for
example depression, can also be effected or facilitated by altering
dopamine mediated neurotransmission. Therefore, compounds of
formula 1 are effective in treating certain mood disorders and mood
episodes based on both cdk5 activity and GSK-3 activity.
Other disorders and conditions the treatment of which can be
effected or facilitated by inhibiting GSK-3 are male fertility and
sperm motility; diabetes mellitus; impaired glucose tolerance;
metabolic syndrome or syndrome X; polycystic ovary syndrome;
adipogenesis and obesity; myogenesis and frailty, for example
age-related decline in physical performance; acute sarcopenia, for
example muscle atrophy and/or cachexia associated with burns, bed
rest, limb immobilization, or major thoracic, abdominal, and/or
orthopedic surgery; sepsis; spinal cord injury; hair loss, hair
thinning, and balding; immunodeficiency; and cancer.
Accordingly, the present invention also provides a pharmaceutical
composition for treating in a mammal, including a human, a disease
or condition selected from male fertility and sperm motility;
diabetes mellitus; impaired glucose tolerance; metabolic syndrome
or syndrome X; polycystic ovary syndrome; adipogenesis and obesity;
myogenesis and frailty, for example age-related decline in physical
performance; acute sarcopenia, for example muscle atrophy and/or
cachexia associated with burns, bed rest, limb immobilization, or
major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair
loss, hair thinning, and balding; and immunodeficiency; which
composition comprises a pharmaceutically acceptable carrier and an
amount of a compound of formula 1 effective in treating said
disease or condition.
The present invention further provides a pharmaceutical composition
for treating in a mammal, including a human, a disease or condition
selected from male fertility and sperm motility; diabetes mellitus;
impaired glucose tolerance; metabolic syndrome or syndrome X;
polycystic ovary syndrome; adipogenesis and obesity; myogenesis and
frailty, for example age-related decline in physical performance;
acute sarcopenia, for example muscle atrophy and/or cachexia
associated with burns, bed rest, limb immobilization, or major
thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss,
hair thinning, and balding; and immunodeficiency; which composition
comprises a pharmaceutically acceptable carrier and an amount of a
compound of formula 1 effective in inhibiting GSK-3.
The present invention also provides a method for treating in a
mammal, including a human, a disease or condition selected from
male fertility and sperm motility; diabetes mellitus; impaired
glucose tolerance; metabolic syndrome or syndrome X; polycystic
ovary syndrome; adipogenesis and obesity; myogenesis and frailty,
for example age-related decline in physical performance; acute
sarcopenia, for example muscle atrophy and/or cachexia associated
with burns, bed rest, limb immobilization, or major thoracic,
abdominal, and/or orthopedic surgery; sepsis; hair loss, hair
thinning, and balding; and immunodeficiency; which method comprises
administering to said mammal an amount of a compound of formula 1
effective in treating said disease or condition.
The present invention also provides a method for treating in a
mammal, including a human, a disease or condition selected from
male fertility and sperm motility; diabetes mellitus; impaired
glucose tolerance; metabolic syndrome or syndrome X; polycystic
ovary syndrome; adipogenesis and obesity; myogenesis and frailty,
for example age-related decline in physical performance; acute
sarcopenia, for example muscle atrophy and/or cachexia associated
with burns, bed rest, limb immobilization, or major thoracic,
abdominal, and/or orthopedic surgery; sepsis; hair loss, hair
thinning, and balding; and immunodeficiency; which method comprises
administering to said mammal an amount of a compound of formula 1
effective in inhibiting GSK-3.
The present invention further provides a method for inhibiting
GSK-3 in a mammal, including a human, which method comprises
administering to said mammal an amount of a compound of formula I1
effective in inhibiting GSK-3.
The present invention further provides a pharmaceutical composition
for treating in a mammal a disorder selected from Alzheimer's
disease, mild cognitive impairment, and age-related cognitive
decline comprising a compound of formula 1 and a COX-II inhibitor
together in an amount effective in treating said disorder, and a
pharmaceutically acceptable carrier.
This invention also provides a method for treating in a mammal a
disorder selected from Alzheimer's disease, mild cognitive
impariment, and age-related cognitive decline which method
comprises administering to said mammal a compound of formula 1 and
a COX-II inhibitor, wherein the combined amounts of the compound of
formula 1 and the COX-II inhibitor are effective in treating said
disorder. The compound of formula 1 and the COX-II inhibitor can be
administered to the mammal at the same time and/or at different
times. Moreover, they may be administered together in a single
pharmaceutical composition or in separate pharmaceutical
compositions.
Moreover, a compound of formula 1 of the invention, or a
pharmaceutically acceptable salt of a compound of formula 1, can be
administered or formulated into a pharmaceutical composition with
one or more anti-depressants or anxiolytic compounds for treatment
or prevention of depression and/or anxiety.
Accordingly, this invention also provides a pharmaceutical
composition for treating depression or anxiety in a mammal
comprising a compound of formula 1 and an NK-1 receptor antagonist
together in an amount effective in treating depression or anxiety,
and a pharmaceutically acceptable carrier.
This invention further provides a method for treating depression or
anxiety in a mammal which method comprises administering to said
mammal a compound of formula 1 and an NK-1 receptor antagonist,
wherein the combined amounts of the compound of formula 1 and the
NK-1 receptor antagonist are effective in treating depression or
anxiety. The compound of formula 1 and the NK-1 receptor antagonist
can be administered to the mammal at the same time and/or at
different times. Moreover, they may be administered together in a
single pharmaceutical composition or in separate pharmaceutical
compositions.
This invention also provides a pharmaceutical composition for
treating depression or anxiety in a mammal comprising a compound of
formula 1 and a 5HT.sub.1D receptor antagonist together in an
amount effective in treating depression or anxiety, and a
pharmaceutically acceptable carrier.
This invention further provides a method for treating depression or
anxiety in a mammal which method comprises administering to said
mammal a compound of formula 1 and a 5HT.sub.1D receptor
antagonist, wherein the combined amounts of the compound of formula
1 and the 5HT.sub.1D receptor antagonist are effective in treating
depression or anxiety. The compound of formula 1 and the 5HT.sub.1D
receptor antagonist can be administered to the mammal at the same
time and/or at different times. Moreover, they may be administered
together in a single pharmaceutical composition or in separate
pharmaceutical compositions.
This invention also provides a pharmaceutical composition for
treating depression or anxiety in a mammal comprising a compound of
formula 1 and a SSRI together in an amount effective in treating
depression or anxiety, and a pharmaceutically acceptable
carrier.
This invention further provides a method for treating depression or
anxiety in a mammal which method comprises administering to said
mammal a compound of formula 1 and a SSRI, wherein the combined
amounts of the compound of formula 1 and the SSRI are effective in
treating depression or anxiety. The compound of formula 1 and the
SSRI can be administered to the mammal at the same time and/or at
different times. Moreover, they may be administered together in a
single pharmaceutical composition or in separate pharmaceutical
compositions.
This invention also provides a pharmaceutical composition for
treating schizophrenia in a mammal comprising a compound of formula
1 and as antipsychotic selected from ziprasidone, olanzapine,
risperidone, L-745870, sonepiprazole, RP 62203, NGD 941,
balaperidone, flesinoxan, and gepirone, together in an amount
effective in treating schizophrenia, and a pharmaceutically
acceptable carrier.
This invention further provides a method for treating schizophrenia
in a mammal which method comprises administering to said mammal a
compound of formula 1 and an antipsychotic selected from
ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP
62203, NGD 941, balaperidone, flesinoxan, and gepirone, wherein the
combined amounts of the cdk5 inhibitor and the antipsychotic are
effective in treating schizophrenia. The compound of formula 1 and
the antipsychotic can be administered to the mammal at the same
time and/or at different times. Moreover, they may be administered
together in a single pharmaceutical composition or in separate
pharmaceutical compositions.
This invention also provides a pharmaceutical composition for
treating a disorder selected from Alzheimer's disease, mild
cognitive impairment, and age-related cognitive decline in a mammal
comprising a compound of formula 1 and an acetylcholinesterase
inhibitor together in an amount effective in treating said
disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal a
disorder selected from Alzheimer's disease, mild cognitive
impairment, and age-related cognitive decline, which method
comprises administering to said mammal a compound of formula 1 and
an acetylcholinesterase inhibitor, wherein the combined amounts of
the compound of formula 1 and the acetylcholinesterase inhibitor
are effective in treating said disorder. The compound of formula 1
and the acetylcholinesterase inhibitor can be administered to the
mammal at the same time and/or at different times.
This invention also provides a pharmaceutical composition for
treating a disease or condition selected from stroke, spinal cord
trauma, traumatic brain injury, multiinfarct dementia, epilepsy,
pain, Alzheimer's disease, and senile dementia comprising a
compound of formula 1 and TPA (tissue plasminogen activator, for
example ACTIVASE) together in an amount effective in treating said
disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal a
disease or condition selected from stroke, spinal cord trauma,
traumatic brain injury, multiinfarct dementia, epilepsy, pain,
Alzheimer's disease, and senile dementia, which method comprises
administering to said mammal a compound of formula 1 and TPA,
wherein the combined amounts of the compound of formula 1 and the
TPA are effective in treating said disease or condition. The
compound of formula 1 and the TPA can be administered to the mammal
at the same time and/or at different times. Moreover, they may be
administered together in a single pharmaceutical composition or in
separate pharmaceutical compositions.
This invention also provides a pharmaceutical composition for
treating a disease or condition selected from stroke, spinal cord
trauma, traumatic brain injury, multiinfarct dementia, epilepsy,
pain, Alzheimer's disease, and senile dementia in a mammal
comprising a compound of formula 1 and NIF (neutrophil inhibitory
factor) together in an amount effective in treating said disorder,
and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal a
disease or condition selected from stroke, spinal cord trauma,
traumatic brain injury, multiinfarct dementia, epilepsy, pain,
Alzheimer's disease, and senile dementia, which method comprises
administering to said mammal a compound of formula 1 and NIF,
wherein the combined amounts of the compound of formula 1 and the
NIF are effective in treating said disease or condition. The
compound of formula 1 and the NIF can be administered to the mammal
at the same time and/or at different times. Moreover, they may be
administered together in a single pharmaceutical composition or in
separate pharmaceutical compositions.
This invention also provides a pharmaceutical composition for
treating a disease or condition selected from Huntington's disease,
stroke, spinal cord trauma, traumatic brain injury, multiinfarct
dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral
induced dementia for example AIDS induced dementia, migraine,
hypoglycemia, urinary incontinence, brain ischemia, multiple
sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's
type, mild cognitive impairment, age-related cognitive decline,
emesis, corticobasal degeneration, dementia pugilistica, Down's
syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease,
prion disease with tangles, progessive supranuclear palsy, lower
lateral sclerosis, and subacute sclerosing panencephalistis in a
mammal comprising a compound of formula 1 and an NMDA receptor
antagonist together in an amount effective in treating said
disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal a
disease or condition selected from Huntington's disease, stroke,
spinal cord trauma, traumatic brain injury, multiinfarct dementia,
epilepsy, amyotrophic lateral sclerosis, pain, viral induced
dementia for example AIDS induced dementia, migraine, hypoglycemia,
urinary incontinence, brain ischemia, multiple sclerosis,
Alzheimer's disease, senile dementia of the Alzheimer's type, mild
cognitive impairment, age-related cognitive decline, emesis,
corticobasal degeneration, dementia pugilistica, Down's syndrome,
myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion
disease with tangles, progessive supranuclear palsy, lower lateral
sclerosis, and subacute sclerosing panencephalistis, which method
comprises administering to said mammal a compound of formula 1 and
an NMDA receptor antagonist, wherein the combined amounts of the
compound of formula 1 and the NMDA receptor antagonist are
effective in treating said disease or condition. The compound of
formula 1 and the NMDA receptor antagonist can be administered to
the mammal at the same time and/or at different times. Moreover,
they may be administered together in a single pharmaceutical
composition or in separate pharmaceutical compositions.
This invention also provides a pharmaceutical composition for
treating a disease or condition selected from stroke, spinal cord
trauma, traumatic brain injury, multiinfarct dementia, epilepsy,
pain, Alzheimer's disease, and senile dementia in a mammal
comprising a compound of formula 1 and a potassium channel
modulator together in an amount effective in treating said
disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal a
disease or condition selected from stroke, spinal cord trauma,
traumatic brain injury, multiinfarct dementia, epilepsy, pain,
Alzheimer's disease, and senile dementia, which method comprises
administering to said mammal a compound of formula 1 and a
potassium channel modulator, wherein the combined amounts of the
compound of formula 1 and the potassium channel modulator are
effective in treating said disease or condition. The compound of
formula 1 and the potassium channel modulator can be administered
to the mammal at the same time and/or at different times. Moreover,
they may be administered together in a single pharmaceutical
composition or in separate pharmaceutical compositions.
The terms "treatment", "treating", and the like, refers to
reversing, alleviating, or inhibiting the progress of the disease
or condition to which such term applies, or one or more symptoms of
such disease or condition. As used herein, these terms also
encompass, depending on the condition of the patient, preventing
the onset of a disease or condition, or of symptoms associated with
a disease or condition, including reducing the severity of a
disease or condition or symptoms associated therewith prior to
affliction with said disease or condition. Such prevention or
reduction prior to affliction refers to administration of the
compound of the invention to a subject that is not at the time of
administration afflicted with the disease or condition.
"Preventing" also encompasses preventing the recurrence of a
disease or condition or of symptoms associated therewith.
"Mammal", as used herein, and unless otherwise indicated, means any
mammal. The term "mammal" includes, for example and without
limitation, dogs, cats, and humans.
"Abnormal cell growth", as used herein, refers to cell growth,
either malignant (e.g. as in cancer) or benign, that is independent
of normal regulatory mechanisms (e.g., loss of contact inhibition).
Examples of benign proliferative diseases are psoriasis, benign
prostatic hypertrophy, human papilloma virus (HPV), and
restinosis.
"Neurodegenerative diseases and conditions", as used herein, refers
to diseases and conditions having associated therewith degeneration
of neurons. Conditions and diseases that are neurodegenerative in
nature are generally known to those of ordinary skill in the
art.
References herein to diseases and conditions "the treatment of
which can be effected or facilitated by altering dopamine mediated
neurotransmission" mean a disease or condition that is caused at
least in part by dopamine neurotransmission, or a disease or
condition that result in abnormal dopamine neurotransmission, thus
contributing to symptoms or manifestations of the disease or
condition.
References herein to diseases and conditions "the treatment of
which can be effected or faciliatated by decreasing cdk5 activity"
mean a disease or condition that is caused at least in part by cdk5
activity, or a disease or condition that results in abnormal cdk5
activity that contributes to symptoms or manifestations of the
disease or condition.
An "amount effective to inhibit cdk5 activity" as used herein
refers to an amount of a compound sufficient to bind to the enzyme
cdk5 with the effect of decreasing cdk5 activity.
An "amount effective to inhibit cdk2 activity" as used herein
refers to an amount of a compound sufficient to bind to the enzyme
cdk2 with the effect of decreasing cdk2 activity.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the formula 1, above, and their pharmaceutically
acceptable salts, can be prepared according to the following
reaction Schemes and discussion. Unless otherwise indicated
R.sup.1, R.sup.3, and R.sup.4 are as defined above. Isolation and
purification of the products is accomplished by standard procedures
which are known to a chemist of ordinary skill.
As used herein, the expression "reaction inert solvent" refers to a
solvent system in which the components do not interact with
starting materials, reagents, or intermediates of products in a
manner which adversely affects the yield of the desired
product.
During any of the following synthetic sequences it may be necessary
and/or desirable to protect sensitive or reactive groups on any of
the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene, Protective Groups in Organic Chemistry, John Wiley &
Sons, 1981; and T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Chemistry, John Wiley & Sons, 1991.
Scheme 1 illustrates methods suitable for preparing compounds of
formula 1 wherein R.sup.3 is a bond or C(.dbd.O). Treatment of an
aldehyde 2 with 5,5-dibromobarbituric acid in an inert organic
solvent such as diethyl ether at about 23.degree. C. for
approximately 13 hours affords .alpha.-bromoaldehyde 3 which can
then be reacted with thiourea C. If R.sup.3 is a bond and R.sup.4
is aryl, heteroaryl, heterocyclic, alkyl, or cycloalkyl, then
compounds of formula 1 are obtained. If R.sup.3 is a bond and
R.sup.4 is H, then aminothiazoles of formula 4 are obtained. These
aminothiazoles (4) can then be reacted with an acid chloride
ClC(.dbd.O)(CR.sup.10 R.sup.11).sub.n R.sup.4, acid anhydride
(R.sup.4 (CR.sup.10 R.sup.11).sub.n C(.dbd.O)).sub.2 O, or an
activated carboxylic acid derivative XC(.dbd.O)(CR.sup.10
R.sup.11).sub.n R.sup.4, wherein the activated carboxylic acid
derivative is prepared from the carboxylic acid
HOC(.dbd.O)(CR.sup.10 R.sup.11).sub.n R.sup.4 and known activating
reagents such as dicyclohexyl carbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
carbonyl diimidazole, 1-propanephosphonic acid cyclic anhyrdide,
alkyl or aryl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic
chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate, or any other such standard literature reagents
in the presence of a base, such as triethylamine,
diisopropylethylamine, pyridine, or 2,6-lutidine, wherein,
1-propanephosphonic acid cyclic anhyrdide and triethylamine are a
preferred combination, from about -78.degree. C. to about
40.degree. C., to afford 1 where R.sup.3 is C(.dbd.O)(CR.sup.10
R.sup.11).sub.n and R.sup.4 is as defined above. Alternatively,
2-aminothiazole 4 can be treated with a base, such as
triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine,
and an alkyl or aryl chloroformate, where diisopropylethylamine and
phenyl chloroformate are a preferred combination, from about
-78.degree. C. to about 40.degree. C. where about -78.degree. C. to
about -40.degree. C. are preferred, to afford 1 where R.sup.3 is
C(.dbd.O)O and R.sup.4 is phenyl. Subsequent treatment of phenyl
carbamate 1 with a primary or secondary amine in a solvent such as
dioxane, dimethylformamide, or acetonitrile, where dioxane is
preferred, at a temperature between about 50.degree. C. and about
110.degree. C., where about 100.degree. C. is preferred, affords
the corresponding urea product 1 where R.sup.3 is
C(.dbd.O)NR.sup.9.
Scheme 2 illustrates an alternative method for preparing compounds
of formula 1. A solution of 2-aminothiazole in tetrahydrofuran at
about -78.degree. C. is treated with 2 equivalents of
n-butyllithium, is stirred approximately 1 hour, 2 equivalents of
chlorotrimethylsilane are added dropwise, then the solution is
warmed to about -10.degree. C. The solution is cooled back to about
-78.degree. C., 1 equivalent of n-butyllithium is added dropwise
and after approximately 10 minutes a solution of a ketone or
aldehyde in tetrahydrofuran is added. Following aqueous work-up and
silica gel chromatography, aminothiazoles of formula 5 are obtained
where A and B are defined as above. Dissolution of 5 in
trifluoroacetic acid followed by treatment with either
triethylsilane or a noble metal catalyst, such as palladium
hydroxide on carbon, and hydrogen gas (3 atmospheres), leads to
hydrogenolysis of the hydroxyl. The aminothiazoles (4) thus
obtained can be treated with a carboxylic acid
(HO(.dbd.O)C(CR.sup.10 R.sup.11).sub.n R.sup.4), propanephosphonic
acid cyclic anhydride, and triethylamine in a solvent such as ethyl
acetate or dichloromethane to afford compounds of formula 1.
Alternatively, 2-aminothiazole 4 can be treated with a base, such
as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine,
and an alkyl or aryl chloroformate, where diisopropylethylamine and
phenyl chloroformate are a preferred combination, from about
-78.degree. C. to about 40.degree. C., where about -78.degree. C.
to about -40.degree. C. are preferred, to afford 1 where R.sup.3 is
C(.dbd.O)O and R.sup.4 is phenyl. Subsequent treatment of phenyl
carbamate 1 with a primary or secondary amine in a solvent such as
dioxane, dimethylformamide, or acetonitrile, where dioxane is
preferred, at a temperature between about 50.degree. C. and about
110.degree. C., where about 100.degree. C. is preferred, affords
the corresponding urea product 1 where R.sup.3 is
C(.dbd.O)NR.sup.9.
Scheme 3 depicts a method for preparing compounds of formula 1
wherein R.sup.1 is ABN-. An aqueous solution consisting of
5-bromo-2-aminothiazole (6) and 20% tetrafluoroboric acid are added
to an aqueous slurry of copper powder and sodium nitrite at about
0.degree. C., followed by warming to about 23.degree. C. Standard
work-up and purification by radial chromatography afford
5-bromo-2-nitrothiazole 7. Treatment of 7 with triethylamine and
ABNH hydrochloride in dimethylsulfoxide at about 60.degree. C.
affords 8. Dissolution of 8 in a solvent such as ethyl acetate and
treatment with palladium on carbon and hydrogen gas (3 atmospheres)
affords aminothiazole 4. The aminothiazoles thus obtained can be
treated with a carboxylic acid (HO(.dbd.O)C(CR.sup.10
R.sup.11).sub.n R.sup.4), propanephosphonic acid cyclic anhydride,
and triethylamine in a solvent such as ethyl acetate or
dichloromethane to afford compounds of formula 1.
Scheme 4 depicts a method for preparing compounds of formula 1
wherein R.sup.1 is nitrogen-substituted cycloalkyl. A dry solution
of cyclobutanone-3-carboxylic acid 9 in tetrahydrofuran is treated
with diphenylphosphoryl azide and triethylamine at about 23.degree.
C. and is warmed at about 60.degree. C. After nitrogen evolution
has ceased, benzyl alcohol is added to provide 10. A solution of
2-aminothiazole in tetrahydrofuran at about -78.degree. C. is
treated with 2 equivalents of n-butyllithium, is stirred
approximately 1 hour, 2 equivalents of chlorotrimethylsilane are
added dropwise, then the solution is warmed to about -10.degree. C.
The solution is cooled back to about -78.degree. C., 1 equivalent
of n-butyllithium is added dropwise and after approximately 10
minutes a solution of ketone 10 in tetrahydrofuran is added.
Following aqueous work-up and silica gel chromatography,
aminothiazole of formula 5 is obtained. Treatment of 5 in methylene
chloride--trifluoroacetic acid with triethylsilane yields 4.
Removal of the benzyloxycarbonyl protecting group with
methanesulfonic acid (8 equiv.) in trifluoroacetic acid followed by
selective acylation of the cycloalkyl amine with an acid anhydride
R.sup.8 C(.dbd.O)OC(.dbd.O)R.sup.8 and triethylamine in methylene
chloride gives 4. Acylation of the aminothiazole nitrogen can be
accomplished by mixing a carboxylic acid (HO(.dbd.O)C(CR.sup.10
R.sup.11).sub.n R.sup.4), propanephosphonic acid cyclic anhydride,
and triethylamine in a solvent such as ethyl acetate or
dichloromethane to afford compounds of formula 1. ##STR3## ##STR4##
##STR5## ##STR6##
Pharmaceutically acceptable salts of a compound of formula 1 can be
prepared in a conventional manner by treating a solution or
suspension of the corresponding free base or acid with one chemical
equivalent of a pharmaceutically acceptable acid or base.
Conventional concentration or crystallization techniques can be
employed to isolate the salts. Illustrative of suitable acids are
acetic, lactic, succinic, maleic, tartaric, citric, gluconic,
ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric,
hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids
such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and
related acids. Illustrative bases are sodium, potassium, and
calcium.
A compound of this invention may be administered alone or in
combination with pharmaceutically acceptable carriers, in either
single or multiple doses. Suitable pharmaceutical carriers include
inert solid diluents or fillers, sterile aqueous solutions and
various organic solvents. The pharmaceutical compositions formed by
combining a compound of formula 1 or a pharmaceutically acceptable
salt thereof can then be readily administered in a variety of
dosage forms such as tablets, powders, lozenges, syrups, injectable
solutions and the like. These pharmaceutical compositions can, if
desired, contain additional ingredients such as flavorings,
binders, excipients and the like. Thus, for purposes of oral
administration, tablets containing various excipients such as
sodium citrate, calcium carbonate and calcium phosphate may be
employed along with various disintegrants such as starch,
methylcellulose, alginic acid and certain complex silicates,
together with binding agents such as polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as
magnesium stearate, sodium lauryl sulfate and talc are often useful
for tabletting purposes. Solid compositions of a similar type may
also be employed as fillers in soft and hard filled gelatin
capsules. Preferred materials for this include lactose or milk
sugar and high molecular weight polyethylene glycols. When aqueous
suspensions or elixirs are desired for oral administration, the
essential active ingredient therein may be combined with various
sweetening or flavoring agents, coloring matter or dyes and, if
desired, emulsifying or suspending agents, together with diluents
such as water, ethanol, propylene glycol, glycerin and combinations
thereof.
For parenteral administration, solutions containing a compound of
this invention or a pharmaceutically acceptable salt thereof in
sesame or peanut oil, aqueous propylene glycol, or in sterile
aqueous solution may be employed. Such aqueous solutions should be
suitably buffered if necessary and the liquid diluent first
rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for
intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
A compound of formula 1 or a pharmaceutically acceptable salt
thereof can be administered orally, transdermally (e.g., through
the use of a patch), parenterally (e.g. intravenously), rectally,
or topically. In general, the daily dosage for treating a
neurodegenerative disease or condition or the disease or condition
the treatment of which can be effected or facilitated by altering
dopamine mediated neurotransmission will generally range from about
0.0001 to about 10.0 mg/kg body weight of the patient to be
treated. The daily dosage for treating cancer or disease or
condition involving abnormal cell growth of a benign nature will
also generally range from about 0.0001 to about 500 mg/kg body
weight of the patient to be treated. As an example, a compound of
the formula 1 or a pharmaceutically acceptable salt thereof can be
administered for treatment of a neurodegenerative disorder to an
adult human of average weight (about 70 kg) in a dose ranging from
about 0.01 mg up to about 1000 mg per day, preferably from about
0.1 to about 500 mg per day, in single or divided (i.e., multiple)
portions. The daily dosage for treating diabetes, sperm motility,
hair loss, or any other disease or condition that can be treated by
inhibiting GSK-3 will generally range from about 0.0001 to about
10.0 mg/kg body weight of the patient to be treated. Variations
based on the aforementioned dosage ranges may be made by a
physician of ordinary skill taking into account known
considerations such as the weight, age, and condition of the person
being treated, the severity of the affliction, and the particular
route of administration chosen.
The compounds of formula 1 and their pharmaceutically acceptable
salts can furthermore also be administered or formulated into a
pharmaceutical composition with an amount of one or more substances
selected from anti-angiogenesis agents, signal transduction
inhibitors, and antiproliferative agents, which amounts are
together effective in inhibiting abnormal cell growth.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase
2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and
COX-II (cyclooxygenase II) inhibitors, can be used in conjunction
with a compound of formula 1 in the methods and pharmaceutical
compositions described herein for treatment of abnormal cell
growth, including cancer. Examples of useful COX-II inhibitors
include CELEBREX.TM. (celecoxib), valdecoxib, and rofecoxib.
Examples of useful matrix metalloproteinase inhibitors are
described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583
(published Mar. 7, 1996), European Patent Application No.
97304971.1 (filed Jul. 8, 1997), European Patent Application No.
99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26,
1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918
(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998),
WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul.
16, 1998), European Patent Publication 606,046 (published Jul. 13,
1994), European Patent Publication 931,788 (published Jul. 28,
1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published
Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667
(published Jun. 17, 1999), PCT International Application No.
PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application
No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent
application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional
Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.
5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued
Jan. 19, 1999), and European Patent Publication 780,386 (published
Jun. 25, 1997), all of which are incorporated herein in their
entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are
those that have little or no activity inhibiting MMP-1. More
preferred, are those that selectively inhibit MMP-2 and/or MMP-9
relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3,
MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and
MMP-13).
Some specific examples of MMP inhibitors useful in the present
invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds
recited in the following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-
amino]-propionic acid;
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.
1]octane-3-carboxylic acid hydroxyamide; (2R, 3R)
1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pip
eridine-2-carboxylic acid hydroxyamide;
4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic
acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-a
mino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic
acid hydroxyamide; (R)
3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxyli
c acid hydroxyamide; (2R, 3R)
1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pip
eridine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethy
l)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-py
ran-4-yl)-amino]-propionic acid;
3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.
1]octane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.
1]octane-3-carboxylic acid hydroxyamide; and (R)
3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxyli
c acid hydroxyamide; and pharmaceutically acceptable salts and
solvates of said compounds.
Other anti-angiogenesis agents, including other COX-II inhibitors
and other MMP inhibitors, can also be used in the present
invention.
The effective amount of a COX-II inhibitor in combination with a
cdk5 inhibitor, for example a compound of formula 1, can generally
be determined by a person of ordinary skill. A proposed daily
effective dose range for a COX-II inhibitor in combination with a
compound of formula 1 is from about 0.1 to about 25 mg/kg body
weight. The effective daily amount of the compound of formula 1
generally will be between about 0.0001 to about 10 mg/kg body
weight. In some instances the amount of COX-II inhibitor and/or
compound of formula 1 in the combination may be less than would be
required on an individual basis to achieve the same desired effect
in inhibiting abnormal cell growth.
A compound of formula 1 can also be used with signal transduction
inhibitors, such as agents that can inhibit EGFR (epidermal growth
factor receptor) responses, such as EGFR antibodies, EGF
antibodies, and molecules that are EGFR inhibitors; VEGF (vascular
endothelial growth factor) inhibitors; and erbB2 receptor
inhibitors, such as organic molecules or antibodies that bind to
the erbB2 receptor, for example, HERCEPTIN.TM. (Genentech, Inc. of
South San Francisco, Calif., USA). Such combinations are useful for
treating and preventing abnormal cell growth, including cancer, as
described herein.
EGFR inhibitors are described in, for example in WO 95/19970
(published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO
98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498
(issued May 5, 1998), and such substances can be used in the
present invention as described herein. EGFR-inhibiting agents
include, but are not limited to, the monoclonal antibodies C225 and
anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y.,
USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer
Ingelheim), MDX-447 (Medarex Inc. of Annandale, N.J., USA), and
OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA),
VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of
Hopkinton, Mass.). These and other EGFR-inhibiting agents can be
used in the present invention.
VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of
South San Francisco, Calif., USA), can also be combined with a
compound of formula 1. VEGF inhibitors are described in, for
example in WO 99/24440 (published May 20, 1999), PCT International
Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613
(published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999),
U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356
(published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16,
1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat.
No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar.
4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596
(published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO
98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8,
1999), and WO 98/02437 (published Jan. 22, 1998), all of which are
incorporated herein in their entireties by reference. Other
examples of some specific VEGF inhibitors useful in the present
invention are IM862 (Cytran Inc. of Kirkland, Wash., USA);
anti-VEGF monoclonal antibody of Genentech, Inc. of South San
Francisco, Calif.; and angiozyme, a synthetic ribozyme from
Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These
and other VEGF inhibitors can be used in the present invention as
described herein.
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc),
and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc.
of The Woodlands, Tex., USA) and 2B-1 (Chiron), can also be
combined with a compound of formula 1, for example those indicated
in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published
Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437
(published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997),
WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458
(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,
1999), which are all hereby incorporated herein in their entireties
by reference. ErbB2 receptor inhibitors useful in the present
invention are also described in U.S. Provisional Application No.
60/117,341, filed Jan. 27, 1999, and in U.S. Provisional
Application No. 60/117,346, filed Jan. 27, 1999, both of which are
incorporated in their entireties herein by reference. The erbB2
receptor inhibitor compounds and substances described in the
aforementioned PCT applications, U.S. patents, and U.S. provisional
applications, as well as other compounds and substances that
inhibit the erbB2 receptor, can be used with a compound of formula
1, in accordance with the present invention.
A compound of formula 1, can also be used with other agents useful
in treating abnormal cell growth or cancer, including, but not
limited to, agents capable of enhancing antitumor immune responses,
such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and
other agents capable of blocking CTLA4; and anti-proliferative
agents such as farnesyl protein transferase inhibitors. Specific
CTLA4 antibodies that can be used in the present invention include
those described in U.S. Provisional Application No. 60/113,647
(filed Dec. 23, 1998) which is incorporated by reference in its
entirety, however other CTLA4 antibodies can be used in the present
invention.
The compounds of formula 1 can also be administered in a method for
inhibiting abnormal cell growth in a mammal in combination with
radiation therapy. Techniques for administering radiation therapy
are known in the art, and these techniques can be used in the
combination therapy described herein. The administration of the
compound of the invention in this combination therapy can be
determined as described herein.
Cdk5 inhibitors, such as compounds of formula 1, can also be
administered in combination with a COX-II inhibitor for treating
Alzheimer's disease, mild cognitive impairment, or age-related
cognitive decline. Specific examples of COX-II inhibitors useful in
this aspect of the invention are provided above, wherein use of a
COX-II inhibitor in combination with a compound of formula 1 for
treatment of abnormal cell growth is described. The effective
amount of a COX-II inhibitor in combination with a cdk5 inhibitor,
for example a compound of formula 1, can generally be determined by
a person of ordinary skill. A proposed effective daily dose range
for a COX-II inhibitor in combination with a compound of formula 1
is from about 0.1 to about 25 mg/kg body weight. The daily
effective amount of the compound of formula 1 generally will be
between about 0.0001 to about 10 mg/kg body weight. In some
instances the amount of COX-II inhibitor and/or the amount of
compound of formula 1 in the combination may be less than would be
required on an individual basis to achieve the same desired effect
in treating Alzheimer's disease, mild cognitive impairment, or
age-related cognitive decline.
Cdk5 inhibitors, such as compounds of formula 1, can also be
administered in combination with an NK-1 receptor antagonist for
treatment of depression or anxiety. An NK-1 receptor antagonist, as
recited herein, is a substance that is able to antagonize NK-1
receptors, thereby inhibiting tachykinin-mediated responses, such
as responses mediated by substance P. Various NK-1 receptor
antagonists are known in the art, and any such NK-1 receptor
antagonist can be utilized in the present invention as described
above in combination with a cdk5 inhibitor, for example a compound
of formula 1. NK-1 receptor antagonists are described in, for
example, U.S. Pat. No. 5,716,965 (issued Feb. 10, 1998); U.S. Pat.
No. 5,852,038 (issued Dec. 22, 1998); WO 90/05729 (International
Publication Date May 31, 1990); U.S. Pat. No. 5,807,867 (issued
Sep. 15, 1998); U.S. Pat. No. 5,886,009 (issued Mar. 23, 1999);
U.S. Pat. No. 5,939,433 (issued Aug. 17, 1999); U.S. Pat. No.
5,773,450 (issued Jun. 30, 1998); U.S. Pat. No. 5,744,480 (issued
Apr. 28, 1998); U.S. Pat. No. 5,232,929 (issued Aug. 3, 1993); U.S.
Pat. No. 5,332,817 (issued Jul. 26, 1994); U.S. Pat. No. 5,122,525
(issued Jun. 16, 1992), U.S. Pat. No. 5,843,966 (issued Dec. 1,
1998); U.S. Pat. No. 5,703,240 (issued Dec. 30, 1997); U.S. Pat.
No. 5,719,147 (issued Feb. 17, 1998); and U.S. Pat. No. 5,637,699
(issued Jun. 10, 1997). Each of the foregoing U.S. patents and the
foregoing published PCT International Application are incorporated
in their entireties herein by reference. The compounds described in
said references having NK-1 receptor antagonizing activity can be
used in the present invention. However, other NK-1 receptor
antagonists can also be used in this invention.
The effective amount of an NK-1 receptor antagonist in combination
with a compound of formula 1 can generally be determined by a
person of ordinary skill. A proposed effective daily dose range for
an NK-1 receptor antagonist in combination with a compound of
formula 1 is from about 0.07 to about 21 mg/kg body weight. The
effective amount of the compound of formula 1 generally will be
between about 0.0001 to about 10 mg/kg body weight. In some
instances the amount of NK-1 receptor antagonist and/or the amount
of compound of formula 1 in the combination may be less than would
be required on an individual basis to achieve the same desired
effect in treating depression or anxiety.
The subject invention also provides combining a compound of formula
1 with a 5HT.sub.1D receptor antagonist for treatment of depression
or anxiety. A 5HT.sub.1D receptor antagonist, as recited herein, is
a substance that antagonizes the 5HT.sub.1D subtype of serotonin
receptor. Any such substance can be used in the present invention
as described above in combination with a compound of formula 1.
Substances having 5HT.sub.1D receptor antagonizing activity can be
determined by those of ordinary skill in the art. For example,
5HT.sub.1D receptor antagonists are described in WO 98/14433
(International Publication Date Apr. 9, 1998); WO 97/36867
(International Publication Date Oct. 9, 1997); WO 94/21619
(International Publication Date Sep. 29, 1994); U.S. Pat. No.
5,510,350 (issued Apr. 23, 1996); U.S. Pat. No. 5,358,948 (issued
Oct. 25, 1994); and GB 2276162 A (published Sep. 21, 1994). These
5HT.sub.1D receptor antagonists, as well as others, can be used in
the present invention. The aforementioned published patent
applications and patents are incorporated herein by reference in
their entireties.
The effective amount of a 5HT.sub.1D receptor antagonist in
combination with a cdk5 inhibitor, for example a compound of
formula 1, can generally be determined by a person of ordinary
skill. A proposed effective daily dose range for a 5HT.sub.1D
receptor antagonist in combination with a compound of formula 1 is
from about 0.01 to about 40 mg/kg body weight. The effective daily
amount of the compound of formula 1 generally will be between about
0.0001 to about 10 mg/kg body weight. In some instances the amount
of 5HT.sub.1D receptor antagonist and/or the amount of compound of
formula 1 in the combination may be less than would be required on
an individual basis to achieve the same desired effect in treating
depression or anxiety.
This invention also provides a pharmaceutical composition and
method for treating depression or anxiety in a mammal comprising a
compound of formula 1 and a SSRI. Examples of SSRIs that can be
combined in a method or pharmaceutical composition with cdk5
inhibitors, for example compounds of formula 1 and their
pharmaceutically acceptable salts include, but are not limited to,
fluoxetine, paroxetine, sertraline, and fluvoxamine. Other SSRIs
may be combined or administered in combination with a compound of
formula 1 or a pharmaceutically acceptable salt thereof. Other
antidepressants and/or anxiolytic agents with which a compound of
formula 1 may be combined or administered include WELLBUTRIN,
SERZONE and EFFEXOR.
The effective amount of a SSRI in combination with a compound of
formula 1 can generally be determined by a person of ordinary
skill. A proposed effective daily dose range for a SSRI in
combination with a compound of formula 1 is from about 0.01 to
about 500 mg/kg body weight. The effective daily amount of the
compound of formula 1 generally will be between about 0.0001 to
about 10 mg/kg body weight. In some instances the amount of SSRI
and/or the amount of compound of formula 1 in the combination may
be less than would be required on an individual basis to achieve
the same desired effect in treating depression or anxiety.
A cdk5 inhibitor, for example a compound of formula 1, or a
pharmaceutically acceptable salt thereof, can also be combined with
one or more antipsychotic agents, for example a dopaminergic agent,
for the treatment of diseases or conditions the treatment of which
can be effected or facilitated by altering dopamine
neurotransmission, such as schizophrenia. Examples of
antipsychotics with which a compound of the invention can be
combined include ziprasidone
(5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihyd
ro-2H-indol-2-one; U.S. Pat. Nos. 4,831,031 and 5,312,925);
olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H-thieno (2,3b)
(1,5)benzodiazepine; U.S Pat. Nos. 4,115,574 and 5,229,382);
risperidone (3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)
-1-piperidinyl]ethyl]6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin
-4-one; U.S. Pat. No. 4,804,663); L-745870
(3-(4-(4-chlorophenyl)piperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine;
U.S. Pat. No. 5,432,177); sonepiprazole
(S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide;
U.S. Pat. No. 5,877,317); RP 62203 (fananserin;
2-(3-(4-(4-fluorophenyl)-1-piperazinyl)propyl)naphtho(1,8-c,d)isothiazole-
1,1-dioxide; U.S. Pat. No. 5,021,420); NGD 941 (U.S. Pat. Nos.
5,633,376 and 5,428,165); balaperidone
((1.alpha.,5.alpha.,6.alpha.)-3-(2-(6-(4-fluorophenyl)-3-azabicyclo(3.2.
0)hept-3-yl)ethyl)-2,4(1H,3H)-quinazolinedione; U.S. Pat. No.
5,475,105); flesinoxan
((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1,4-benzodioxanyl)]-1-piperazinyl
]ethyl]benzamide; U.S. Pat. No. 4,833,142); and gepirone
(4,4-dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidined
ione; U.S. Pat. No. 4,423,049). The patents recited above in this
paragraph are each incorporated herein by reference in their
entireties. The effective daily amount of the compound of formula 1
generally will be between about 0.0001 to about 10 mg/kg body
weight. The amount of any of the aforementioned antipsychotic
agents contemplated for use in combination with a compound of
formula 1 is generally the amount known in the art to be useful for
treating psychotic conditions. However, in some instances, the
amount of the antipsychotic and/or the amount of compound of
formula 1 in the combination may be less than would be required on
an individual basis to achieve the same desired effect in treating
depression or anxiety. It is furthermore to be understood that the
present invention also encompasses combining a compound of formula
1 with antipsychotic or dopaminergic other than those in the
aforementioned list.
A proposed amount for sonepiprazole in the above-described
combination with a compound of formula 1 is from about 0.005 to
about 50 mg/kg body weight of the patient per day. A proposed
amount of RP 62203 in such combination is from about 0.20 to about
6 mg/kg body weight of the patient per day. A proposed amount of
NGD 941 in such combination is from about 0.1 to about 140 mg/kg of
body weight per day. A proposed amount of balaperidone in such
combination is from about 1 to about 100 mg/kg body weight per day.
A proposed amount of flesinoxan in such combination is from about
0.02 to about 1.6 mg/kg body weight per day. A proposed amount for
gepirone in such combination is from about 0.01 to about 2 mg/kg
body weight per day. A proposed amount of L-745870 in such
combination is from about 0.01 to about 250 mg/kg body weight per
day, preferably from about 0.05 to about 100 mg/kg body weight per
day. A proposed amount of risperidone in such combination is from
about 0.05 to about 50 mg/kg body weight per day. A proposed amount
of olanzapine in such combination is from about 0.0005 to about 0.6
mg/kg body weight per day. A proposed amount of ziprasidone in such
combination is from about 0.05 to about 10 mg/kg body weight per
day. In some instances for each of the aforementioned combinations,
however, the amount of each specific ingredient in the combination
may be less than would be required on an individual basis to
achieve the same desired effect in treating a psychotic
condition.
This invention also provides a pharmaceutical composition and
method for treating Alzheimer's disease, mild cognitive impairment,
or age-related cognitive decline comprising a compound of formula 1
and an acetylcholinesterase inhibitor. Acetylcholinesterase
inhibitors are known in the art, and any such acetylcholinesterase
inhibitor can be used in the above-described pharmaceutical
composition or method. Examples of acetylcholinesterase inhibitors
that can be used in this invention are ARICEPT (donepezil; U.S.
Pat. No. 4,895,841); EXELON (rivastigmine
((S)-[N-ethyl-3-[1-(dimethylamino)ethyl]phenyl carbamate); U.S.
Pat. Nos. 5,603,176 and 4,948,807); metrifonate
((2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester;
U.S. Pat. Nos. 2,701,225 and 4,950,658); galantamine (U.S. Pat. No.
4,663,318); physostigmine (Forest, USA); tacrine
(1,2,3,4-tetrahydro-9-acridinamine; U.S. Pat. No. 4,816,456);
huperzine A
(5R-(5.alpha.,9.beta.,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-me
thyl-5,9-methaneocycloocta(b)pyridin-2-(1 H)-one); and icopezil
(5,7-dihydro-3-(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)
-1,2-benzisoxazol-6-one; U.S. Pat. No. 5,750,542 and WO 92/17475).
The patents and patent applications recited above in this paragraph
are herein incorporated by reference in their entireties.
The effective amount of an acetylcholinesterase inhibitor in
combination with a compound of formula 1 can generally be
determined by a person of ordinary skill. A proposed effective
daily dose range for an acetylcholinesterase inhibitor in
combination with a compound of formula 1 is from about 0.01 to
about 10 mg/kg body weight. The effective daily amount of the
compound of formula 1 generally will be between about 0.0001 to
about 10 mg/kg body weight. In some instances the amount of
acetylcholinesterase inhibitor and/or the amount of compound of
formula 1 in the combination may be less than would be required on
an individual basis to achieve the same desired effect in treating
Alzheimer's disease, mild cognitive impairment, or age-related
cognitive decline.
The present invention also provides for combining a compound of
formula 1 with neuroprotectants, for example NMDA receptor
antagonists, for treatment of Huntington's disease, stroke, spinal
cord trauma, traumatic brain injury, multiinfarct dementia,
epilepsy, amyotrophic lateral sclerosis, pain, viral induced
dementia for example AIDS induced dementia, migraine, hypoglycemia,
urinary incontinence, brain ischemia, multiple sclerosis,
Alzheimer's disease, senile dementia of the Alzheimer's type, mild
cognitive impairment, age-related cognitive decline, emesis,
corticobasal degeneration, dementia pugilistica, Down's syndrome,
myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion
disease with tangles, progessive supranuclear palsy, lower lateral
sclerosis, or subacute sclerosing panencephalistis. Examples of
NMDA receptor antagonists that can be used in the present invention
include
(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propano
l (U.S. Pat. No. 5,272,160), eliprodil (U.S. Pat. No. 4,690,931),
and gavestenel (U.S. Pat. No. 5,373,018). Other NMDA receptor
antagonists, which can also be used in the present invention, are
described in U.S. Pat. Nos. 5,373,018; 4,690,931; 5,272,160;
5,185,343; 5,356,905; 5,744,483; WO 97/23216; WO 97/23215; WO
97/23214; WO 96/37222; WO 96/06081; WO 97/23458; WO 97/32581; WO
98/18793; WO 97/23202; and U.S. Ser. No. 08/292,651 (filed Aug. 18,
1994). The aforementioned patents and patent applications are each
hereby incorporated by reference in their entireties.
The effective daily amount of the compound of formula 1 in the
combination with an NMDA receptor antagonist generally will be
between about 0.0001 to about 10 mg/kg body weight. The amount of
the NMDA receptor antagonist contemplated for use in combination
with a compound of formula 1 for treatment of any of the
aforementioned disorders, for example Alzheimer's disease, is
generally within the range of from about 0.02 mg/kg/day to about 10
mg/kg/day. However, in some instances, the amount of the NMDA
antagonist and/or the amount of compound of formula 1 in the
combination may be less than would be required on an individual
basis to achieve the same desired effect in treating said
disorders.
The subject invention also provides for combining a compound of
formula 1 with certain substances capable of treating a stroke or
traumatic brain injury, such as TPA, NIF, or potassium channel
modulators, for example BMS-204352. Such combinations are useful
for treating neurodegenerative disorders such as stroke, spinal
cord trauma, traumatic brain injury, multiinfarct dementia,
epilepsy, pain, Alzheimer's disease, and senile dementia, for
example.
For the above-described combination therapies and pharmaceutical
compositions, the effective amounts of the compound of the
invention and of the other agent can generally be determined by
those of ordinary skill in the art, based on the effective amounts
for the compounds described herein and those known or described for
the other agent known in the art, for example the amounts described
in the above-recited patents and patent application incorporated
herein. The formulations and routes of administration for such
therapies and compositions can be based on the information
described herein for compositions and therapies comprising a
compound of the invention as the sole active agent and on
information provided for the other agent in combination
therewith.
A specific compound of formula 1 can be determined to inhibit cdk2,
cdk5, or GSK-3 using biological assays known to those of ordinary
skill in the art, for example the assays described below.
The specific activity of a compound of formula 1 for inhibition of
cdk5 or cdk2 can, for example, be ascertained by means of the
following assays using materials available to those of ordinary
skill in the art:
Enzyme activities were assayed as the incorporation of [33P] from
the gamma phosphate of [33P]ATP (Amersham, cat. no. AH-9968) into
biotinylated peptide substrate PKTPKKAKKL. Reactions were carried
out in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl2, 0.1
mM Na3VO4, and 1 mM DTT. The final concentration of ATP was 0.5 uM
(final specific radioactivity of 4 uCi/nmol), and the final
concentration of substrate was 0.75 uM. Reactions, initiated by the
addition of either cdk5 and activator protein p25 or cdk2 and
activator cyclin E, were carried out at room temperature for 60
minutes. Reactions were stopped by addition of 0.6 volume of buffer
containing (final concentrations): 2.5 mM EDTA, 0.05%Triton-X 100,
100 uM ATP, and 1.25 mg/ml streptavidin coated SPA beads (Amersham
cat. no. RPNQ0007). Radioactivity associated with the beads was
quantified by scintillation counting.
The specific activity of a compound of formula 1 for inhibition of
GSK-3 can be determined in both cell-fee and cell-based assays,
both of which are described in the art (see, for example, WO
99/65897). A cell-free assay can be carried out in general by
incubating GSK-3 with a peptide substrate, radiolabeled ATP (such
as, for example, .gamma..sup.33 P- or .gamma..sup.32 -P-ATP, both
available from Amersham, Arlington Heights, Ill.), magnesium ions,
and the compound to be assayed. The mixture is incubated for a
period of time to allow incorporation of radiolabeled phosphate
into the peptide substrate by GSK-3 activity. The reaction mixture
is washed to remove unreacted radiolabeled ATP, typically after
first transferring all or a portion of the enzyme reaction mixture
to a well that contains a uniform amount of a ligand that is
capable of binding to the peptide substrate. The amount of .sup.33
P or .sup.32 P remaining in each well after washing is then
quantified to determine the amount of radiolabeled phosphate
incorporated into the peptide substrate. Inhibition is observed as
a reduction, relative to a control, in the incorporation of
radiolabeled phosphate into the peptide substrate. An example of a
suitable GSK-3 peptide substrate for an assay is the SGSG-linked
CREB peptide sequence, derived from the CREB DNA binding protein,
described in Wang, et al., Anal. Biochem., 220:397-402 (1994).
Purified GSK-3 for an assay may, for example, be obtained from
cells transfected with a human GSK-3.beta. expression plasmid as
described in, for example Stambolic, et al., Current Biology
6:1664-68 (1996).
WO 99/65897; Wang, et al., and Stambolic, et al. are incorporated
in their entireties herein by reference.
All of the title compounds of the following Examples had an
IC.sub.50 inhibiting peptide substrate phosphorylation of less than
about 50 .mu.M when assayed for cdk5 inhibition according to the
preceding assay.
All of the title compounds of the following Examples had an
IC.sub.50 inhibiting peptide substrate phosphorylation of less than
about 50 .mu.M when assayed for cdk2 inhibition according to the
preceding assay.
All of the title compounds of the following Examples had an
IC.sub.50 for inhibition of GSK-3.beta. of less than about 50
.mu.M.
The following Examples illustrate the present invention. It is to
be understood, however, that the invention, as fully described
herein and as recited in the claims, is not intended to be limited
by the details of the following Examples.
EXAMPLES
Preparation 1
1-(2-Amino-thiazol-5-yl)-cyclobutanol
A solution of 2-aminothiazole (7.1 g, 71 mmol) in THF (360mL)
cooled to -78.degree. C. was treated dropwise with n-BuLi (56.18
mL, 142 mmol) while maintaining an internal temperature less than
or about equal to -60.degree. C. After addition was completed, the
solution was treated dropwise with chlorotrimethylsilane (18 mL,
142 mmol). The reaction solution was warmed to -10.degree. C., then
was cooled back to -78.degree. C. n-Butyllithium (28.4 mL, 71 mmol)
was added dropwise and after 10 minutes, cyclobutanone (5.33 mL, 71
mmol) was added dropwise. The solution was stirred for 1 hour at
-78.degree. C., was quenched with saturated ammonium chloride
solution, and was warmed to 23.degree. C. The reaction mixture was
extracted with ethyl acetate (300 mL). The organic layer was washed
with brine, was dried (MgSO.sub.4), was filtered, and solvent was
removed in vacuo. The resulting residue was purified by silica gel
chromatography (15:1.fwdarw.7:1 CHCl.sub.3 --MeOH) to afford 7.24 g
of 1-(2-amino-thiazol-5-yl)cyclobutanol. .sup.1 HNMR (400 MHz,
DMSO-D6) .delta. 6.78 (s, 1H), 6.70 (s,2H), 5.58 (s,1H), 22 (m,4H),
1.69 (m, 1H), 1.50 (m,1H).
Preparation 2
5-Cyclobutyl-thiazol-2-ylamine
A solution of 1-(2-amino-thiazol-5-yl)cyclobutanol (Preparation 1;
6.6 g, 39 mmol) in trifluoroacetic acid (150 mL) was treated with
20% palladium hydroxide on carbon (2.3 g). The mixture was
evacuated and purged with nitrogen (3 times), then was evacuated
and purged with hydrogen gas (50 psi). The mixture was shaken for
24 hours and was evacuated and purged with nitrogen. The mixture
was then filtered through Celite which was rinsed with methanol.
The organic solvent was removed in vacuo, ethylacetate was added,
followed by 29% ammonium hydroxide solution. The aqueous and
organic layers were separated and the aqueous layer was extracted
with ethylacetate. The combined organic layers were washed with
brine, were dried (MgSO.sub.4), were filtered, and the solvent was
removed in vacuo. The resulting residue was purified by silica gel
chromatography (40:1:1 CHCl.sub.3 --MeOH--NH.sub.4 OH) to afford
4.75 g of 5-cyclobutyl-thiazol-2-ylamine, the title compound.
.sup.1 HNMR (400 MHz, DMSO-d6): 6.66(s,2H), 6.57(s, 2H), 3.43
(m,1H), 2.20 (m,2H), 1.98-1.7 (m,4H).
Example 1
N-(5-Cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide
A solution of 5-cyclobutyl-thiazol-2-ylamine (Preparation 2; 30 mg,
0.195 mmol) was treated with triethylamine (81 .mu.l, 0.585 mmol),
6-quinolylaceticacid (40 mg, 0.214 mmol) and propylphosphonic acid
cyclic anhydride (T.sub.3 P, 126 mL, 0.214 mmol). After 2 hours, an
additional 0.2 equiv. of T.sub.3 P (22 .mu.l) was added and the
reaction was complete by TLC after 15 minutes. The reaction mixture
was diluted with CHCl.sub.3, was washed with saturated aqu.
NaHCO.sub.3, and was dried (MgSO.sub.4), filtered and concentrated
in vacuo. The resulting residue was purified by silica gel
chromatography (40:1 CHCl.sub.3 --MeOH) to afford 55 mg of
N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide, the title
compound, as a white solid.
.sup.1 HNMR (400 MHz; CDCl.sub.3) .delta. 8.88 (dd, J=1.66, 4.15
Hz; 1H), 8.08 (s,1H), 8.06 (s,1H), 7.72 (s,1H), 7.65(m,1H), 7.37
(m,1H), 7.07 (d,J=0.83 Hz,1H), 4.01 (s,2H), 3.62(m,1H), 2.36(m,2H),
2.12(m,2H), 1.97(m,1H), 1.82(m,2H). LRMS m/z (APCl.sup.+) 324.0
(M+H).sup.+.
Example 2
(5-Cyclobutyl-thiazol-2-yl)-carbamic acid phenyl ester
A solution of 2-amino-5-cyclobutyl thiazole (Preparation 2; 2.5 g,
1 6 mmol) and diisopropylethylamine (2.82 mL, 16 mmol) in methylene
chloride (200 mL) was cooled to -78.degree. C. and
phenylchloroformate (2 mL, 16 mmol) was added dropwise. The
reaction mixture was slowly warmed to 23.degree. C., was stirred
for 1 hour at this temperature, than was washed with aqueous
saturated sodium bicarbonate (2 times) and brine (1 time), was
dried (MgSO.sub.4), was filtered, and was concentrated in vacuo.
The resulting white solid was purified by silica gel chromatography
(5:1 CHCl.sub.3 -hexanes) to afford 3.5 g of the title compound as
a white solid.
.sup.1 HNMR (400 MHz, CDCl.sub.3): .delta. 7.42 (m,2H), 7.26
(m,3H), 7.11(s,1H), 3.62(m,1H), 2.37 (m,2H), 2.13 (m,2H), 1.97
(m,1H), 1.89 (m,1H).
Example 3
1-(5-Cyclobutyl-thiazol-2-yl)-3-(2-methyl-quinolin-6-yl)-urea
A solution of (5-cyclobutyl-thiazol-2-yl)-carbamic acid phenyl
ester (Example 2; 35 mg, 0.128 mmol) and 6-amino-2-methyl-quinoline
(50 mg, 0.128 mmol) in 1,4-dioxane (500 .mu.l) were heated at about
70.degree. C. for 24 hours. Purification by silica gel
chromatography (1:3 hexanes-ethylacetate; 40:1.fwdarw.20:1
chloroform-methanol) and subsequent conversion to the HCl salt
afforded 40 mg of the title compound. .sup.1 HNMR (400 MHz,
CDCl.sub.3) .delta. 8.11(s,1H), 7.87 (s,7.88,1H), 7.85 (s,1H), 7.45
(d, J=7.6 Hz,1H), 7.16 (d, J=8.4 Hz, 1H), 6.94 (s,1H), 3.55 (m,1
H), 2.67 (s,3H), 2.35 (m,2H), 2.15-1.80 (m,4H). LRMS m/z
(APCl.sup.+) 339.0 (M+H).sup.+.
Preparation 3
(3-Oxo-cyclobutyl)-carbamic acid benzyl ester
A solution of (3-oxo-cyclobutyl)-carboxylic acid (506 mg, 4.4 mmol)
and Et.sub.3 N(734 .mu.l) in 1:1 THF-Toluene (15 mL) was treated
with diphenyl phosphoryl azide (956 .mu.L, 4.4 mmol). The solutions
warmed to 60.degree. C. over ca. 45 minutes, at which point
nitrogen evolution was noted. After 3 hours, benzyl alcohol (500
.mu.L, 4.8 mmol) was added and the solution was kept at 60.degree.
C. for 4 hours. After cooling to room temperature, the solution was
diluted with ethylacetate, was washed with saturated aqueous sodium
bicarbonate (1 time), 0.5NHCl (2 times) NaHCO.sub.3 (1 time), was
dried (MgSO.sub.4), filtered, and was purified by silica gel
chromatography (4:1 Hexanes-Ethylacetate) to afford 405 mg of the
title compound. .sup.1 HNMR(400 MHz, CDCl.sub.3) 7.32 (m,5H), 5.44
(s,1H), 5.08(s,2H) 4.29(m,1H), 3.36(m, 2H), 3.06 (m, 2H). LRMS
(APCl.sup.-) 218.1 (M-H).sup.-.
Preparation 4
[3-(2-Amino-thiazol-5-yl)-3-hydroxy-cyclobutyl]-carbamic acid
benzyl ester
A solution of 2-aminothiazole (350 mg, 3.5 mmol) in THF (26 mL) at
78.degree. C. was treated dropwise with n-BuLi (2.8 mL, 7 mmol) at
such a rate to keep the internal reaction temperature
.ltoreq.-60.degree. C. The solution was stirred 1 hour,
chlorotrimethyl silane was added (888 .mu.L, 7 mmol) (internal
temperature .ltoreq.-60.degree. C.) and the temperature was
increased to -10.degree. C., then was cooled to -78.degree. C.
n-BuLi (1.4 mL, 3.5 mmol) was added dropwise (internal temp
.ltoreq.-60.degree. C.) and after stirring for 10 minutes
Preparation 3 (365 mg, 1.67 mmol) in THF (6 mL) was added dropwise.
After 1 hour at 78.degree. C., aqueous ammonium chloride was added,
the mixture was warmed to 23.degree. C., and was diluted with
ethylacetate. The aqueous and organic layers were separated, the
organic layer was dried (MgSO.sub.4), filtered, and purified by
silica gel chromatography (30:1CHCl.sub.3 --MeOH) to afford 166 mg
of the title compound.
Preparation 5
N-[3-(2-Amino-thiazol-5-yl)-cyclobutyl]-acetamide
A solution of Preparation 4 (960 mg,3 mmol) in methylene
chloride--Trifluoroacetic acid (1:1, 60 mL) was treated with
triethylsilane (1.44 mL, 9 mmol). After 18 hours, more
triethylsilane (1 mL,) was added. After 3 hours, solvent was
removed in vacuo, methylene chloride was added, followed by a small
volume of NH.sub.4 OH to neutralize any acid. The mixture was
adsorbed onto silica gel and was purified by silica gel
chromatography (15:1.fwdarw.10:1 CHCl.sub.3 --MeOH). 445 mg (49%
yield) of ).sup.+ [3-(2-amino-thiazol-5-yl)cyclobutyl]-carbamic
acid benzyl ester was obtained. LRMS m/z (APCl.sup.+) 304
(M+H).sup.+.
A portion of this material (290 mg, 0.96 mmol) was dissolved in
trifluoroacetic acid and was treated with anisole (200 .mu.L, 1.9
mmol) and methane sulfonic acid (498 .mu.L, 7.7 mmol) at 0.degree.
C.). The solution was allowed to warm to 23.degree. C. over 1 hour,
solvent was removed in vacuo, and the residue was then treated with
25% NaOH, solid NaCl, and was extracted with ethylacetate (2
times). The organic layer was dried (MgSO.sub.4), filtered, and
purified by silica gel chromatography to afford 89 mg of
5-(3-amino-cyclobutyl)-thiazol-2-ylamine. LRMS m/z (APCl.sup.+)
170.1 (M+H).sup.+.
A portion of this material (13 mg, 0.077 mmol) was dissolved in
CH.sub.2 Cl.sub.2 -methanol (5:1, 6 mL). Triethylamine (32 .mu.L,
0.23 mmol) was added and a solution of acetic anhydride in CH.sub.2
Cl.sub.2 (0.06M) was added dropwise. Monitoring by TLC (10:1
CHCl.sub.3 --MeOH, 2% NHClOH) was used to determine when all 5M was
consumed. NH.sub.4 OH was added, then the reaction mixture was
adsorbed onto silica gel and was purified by silica gel
chromatography to afford 11 mg of the title compound as a mixture
of cis-trans isomers. .sup.1 HNMR(400 MHz, CD.sub.3 OD) .delta.
7.86(s,1H) 6.67 (s,0.25H), 6.60(s,0.75H), 4.4(m,0.25H), 4.2 (m,
0.75H), 3.5 (m, 0.25H) 3.17(m,0.75H), 2.68(m, 2H), 2.37 (m, 1H),
1.98-1.88(m,4H). LRMS m/z (APCl.sup.+) 212.1 (M+H).sup.+.
Preparation 6
2-Bromo-3-Methylpropanal
A solution of 3-methylpropanal (3 g, 35 mmol, 3.7 mL) in dry
diethyl ether (50 mL) was treated with 5,5-dibromobarbituric acid
(5 g, 17 mmol) and the resulting solution was stirred at 23.degree.
C. for 15 hours, during which a precipitate developed. Pentane (30
mL) was added and the precipitate was filtered off. The solution
was concentrated in vacuo at 19.degree. C., 350 mmHg, during which
a precipitate developed. Pentane (30 mL) was added to the residue
and the precipitate was filtered off. The solution was concentrated
in vacuo at 19.degree. C., 350 mmHg to afford 3.6 g of the title
compound as a volatile oil. .sup.1 HNMR (400 MHz, CDCl.sub.3)
.delta. 9.41 (d,J=3.7 Hz, 1 H), 4.04 (dd, J=6.4, 3.7 Hz, 1H) 1.25
(m, 1H), 1.06(m, 6H).
Example 4
N-[5-(3-Acetylamino-cyclobutyl)-thiazol-2-yl-quinolin-6-yl-acetamide
The procedure to acylate Preparation 5 was the same as that used in
Example 1. 10 mg, 0.047 mmol, of Preparation 5 afforded 15 mg of
the title compound. .sup.1 HNMR (400 MHz, CD.sub.3 OD): .delta.
8.77(m, 1H), 8.26(m, 1H) 7.96(m, 1H), 7.84(s, 1H), 7.74 (d, J=2.1
Hz, 1H), 7.48 (m, 1H) 7.14 (s, 0.25H) 7.06(s, 0.75H), 4.40(m,
0.25H), 4.20 (m, 0.75H), 3.96 (s, 2H), 2.73 (m, 2H), 2.42 (m, 1H),
1.98(m, 2H), 1.88(s,3H) LRMS m/z (APCl.sup.+) 381.0
(M+H).sup.+.
Example 5
(5-Isopropyl-thiazol-2-yl)-(6-methyl-pyridin-2-yl-amine
A mixture of 2-bromo-3-methyl propanal (Preparation 6, 307 mg, 1.87
mmol) and N-(3-methylpyridyl) thiourea (313 mg, 1.87 mmol) in water
(10 mL) was heated at 80.degree. C. for 18 hours. Ammonium
hydroxide was added (pH.apprxeq.11), the mixture was extracted with
ethyl acetate and the organic layer was washed with brine, was
dried (mgSO.sub.4) filtered, and concentrated in vacuo. The
resulting residue was purified by preparative thin layer
chromatography (1:1 hexanes-ethylacetate) to afford 100 mg (23%
yield) of desired product, .sup.1 HNMR(400 MHz, CDCl.sub.3) .delta.
7.44 (t, J=7.7H, 1H), 7.08(s,1H), 6.67 (m, 2H), 3.12 (m, 1H), 2.52
(s, 3H) 1.34 (d,J=6.85, 6H). LRMS m/z (APCl.sup.+) 234.0
(M+H).sup.+.
* * * * *